UNIVERSITY OF VETERINARY AND PHARMACEUTICAL SCIENCES BRNO
FACULTY OF PHARMACY Department of Pharmaceutics
MEDICAL FORMS AND BIOPHARMACY Solid Dosage Forms Kateřina Kubová Aleš Franc Jan Gajdziok Martina Kejdušová David Vetchý
BRNO 2014
UNIVERSITY OF VETERINARY A PHARMACEUTICAL SCIENCES BRNO FACULTY OF PHARMACY Department of Pharmaceutics
MEDICAL FORMS AND BIOPHARMACY
Solid Dosage Forms
Doc. PharmDr. Kateřina Kubová, Ph.D. PharmDr. Aleš Franc, Ph.D. PharmDr. Jan Gajdziok, Ph.D. PharmDr. Martina Kejdušová, Ph.D. Doc. PharmDr. Mgr. David Vetchý Ph.D.
BRNO 2014
Content Content ....................................................................................................................................... 6 1.
Oral solid dosage forms...................................................................................................... 6 1.1
Oral powders, divided and bulk ................................................................................... 6
1.2
Dusting powders ........................................................................................................ 14
1.3
Granules ..................................................................................................................... 18
1.4
Tablets ........................................................................................................................ 25
1.5
Coated tablets ............................................................................................................. 31
1.5.1 Dragees (sugar coated tablets) ................................................................................. 32 1.5.2 Film coated tablets .................................................................................................. 35 1.6
Oral solid dosage forms with controlled release ........................................................ 38
1.6.2 Pellets ...................................................................................................................... 40 2.
Rectal and vaginal drug forms ......................................................................................... 50 2.1
Rectal drugs ................................................................................................................ 50
2.1.1 Suppositories ........................................................................................................... 50 2.2
Vaginal drugs ............................................................................................................. 62
2.2.1 Vaginal pessaries (vaginal globules, vaginal suppositories) ................................... 62 3.
Evaluations ....................................................................................................................... 66 3.1
Uniformity of content of single-dose preparations .................................................... 66
3.2
Uniformity of mass of single-dose preparations ........................................................ 67
3.3
Uniformity of dosage units ........................................................................................ 67
3.4
Particle size distribution ............................................................................................. 72
3.5
Bulk and tapped density ............................................................................................. 73
3.6
Flowability ................................................................................................................. 74
3.7
Friability of uncoated dosage forms ........................................................................... 77
3.8
Resistance to crushing of tablets (hardness) .............................................................. 78
3.9
Disintegration of tablets and capsules ........................................................................ 79
3.10 Dissolution test for oral solid dosage forms ............................................................... 81 3.11 Evaluation of content ................................................................................................. 85
PREFACE The subject “Medical Forms and Biopharmacy” is offered in the curriculum of the Pharmaceutical Faculty of the University of Veterinary and Pharmaceutical Sciences Brno and taught by the Department of Pharmaceutics. Pharmaceutical technology is one of the profile pharmaceutical disciplines, which deals with the composition, formulation, production, evaluation and quality assurance of drugs. It studies the conditions in which active substances and pharmaceutical excipients are transformed into the final form of the medicinal product. It also describes the various rules by which these processes are controlled, ensuring the production of drugs, maintains a level of declared efficiency, stability and safety. The optimization of the technological process of drug production is as important step as the synthesis of the active ingredients or the isolation of unknown compounds are. The main reason for the transformation of active substances into the form of medicinal preparations is the requirement for a drug to be applied in safe and comfortable way, usually by location and in a time-controlled manner. The formulation and production of the final medicinal product is often dependent upon pharmaceutical excipients and their suitable selection. Constitutive excipients usually form the outer appearance of the dosage form as well as its inner structure, and control the application of the drug, ensure the drug’s physico-chemical and microbiological stability, identify the specific product and often regulate the sensory perception of the final product. The identification of factors influencing the bioavailability of the active substance led to the conclusion that medicine and its formulation play a key role in this issue. Pharmaceutical technology, mainly due to the study of the relationship between the form of the medicinal product and drug bioavailability, created a new way for the preparation of advanced generation drugs. Thus, an interdisciplinary field was created - biopharmacy, which combines knowledge about chemically-defined active substances and their pharmacological properties with the field of pharmaceutical technology, which deals with the formulation and design of application forms. Together with the support of the modern knowledge of pharmacodynamics, pharmacokinetics, chronopharmacology and pathophysiology, biopharmaceutical findings are reflected in the development and production of drugs with a controlled and targeted release. The aim of the practical classes from subject Medical Forms and Biopharmacy is to try to give students basic information about the rules and techniques used in the field of prepared 4
dosage forms, both individually and industrially, with an emphasis on practical skills training for the preparation and evaluation of liquid, semisolid and solid dosage forms in the laboratory. This text is based on the Czech language version extended to complement with new knowledge and approaches. Emphasis is placed on trying to generalize the national particularities of the level of European practices, which is closely connected with the use of nomenclature, according to the European Pharmacopoeia.
5
1.
Oral solid dosage forms
1.1 Oral powders, divided and bulk Oral powders are preparations consisting of solid, loose and dry particles to varying degrees of fineness. They are coarse disperse systems of solid particles in air as the external phase. They contain one or more active substances, with or without excipients and, if necessary, colouring matter authorised by the competent authority and flavouring substances. They are generally administered in or with water or another suitable liquid. They may also be swallowed directly. They are presented as single-dose (divided) or multi-dose (non-divided) preparations. The presence of potent and highly potent drugs in multi-dose preparations is not permitted.
Effervescent powders (pulveres effervescentes) Effervescent powders are included with the oral powders. Effervescent powders are presented as single-dose or multi-dose preparations. Generally, they contain acid substances and carbonates or hydrogen carbonates, which react rapidly in the presence of water to release carbon dioxide. They are intended to be dissolved or dispersed in water before administration. They must be stored in an airtight container with desiccant.
Requirements For compounding, the powdered materials with small particles are required, because only these can ensure necessary homogeneity of mixture. Powders of small particle size represent a large surface which leads to increase of dissolution rate enabling good prediction for quick absorption and rapid onset of action.
Preparation procedure Reduction of particle size: Efficient mills, precipitation method or spray drying are used for obtaining powders with required particle size. Mechanical methods of reducing particle size are associated with environment contamination. In industry, workers must be protected against dust inhalation by suitable protective equipments (dust masks, respirators). 6
The reduction of particle size using a mortar and pestle is typical in pharmacy. To obtain a homogenous mixture without grits and agglomerates, powders are to be prepared by careful mixing in ceramic mortars with rough internal surfaces. During the mixing, it is necessary to clean the mortar walls and pestle with a scraper. Homogenisation: Mortar and pestle, planetary mixers, turbula, drum mixers, fluidized air mixers and other equipment are used for mixing which is an important part of powder preparation. The addition of silicon dioxide, lactose and magnesium stearate is used for improving the flow characteristics of oral powders. The other classification of powders is based on the number of active substances. There are simple powders (Pulveres simplices) which consist of one active substance and composite powders (Pulveres compositi) which consist of two or more active substances. Both types can contain other excipients. The powder can be classified according to its particle size (see Table 1). Table 1. Terms to define powder fineness Classification of powder Sieve opening size(µm) Very Coarse > 1000 Coarse 355–1000 Moderately Fine 180–355 Fine 125–180 Very Fine 90–125
Packaging The powders are dispensed according to their use. Non-divided (multi-dose) powders can be packaged in wide-neck bottles and paper or plastic containers. Divided (single-dose) powders are usually filled into hard capsules (filled hard capsules are packaged in paper boxes, wide-neck bottles or plastic jars), a higher amount into paper or plastic packets.
Labelling Oral powders (for swallowing) - white label 7
Bulk powder for preparation of gargles (Oromucosal preparations) – red label for external administration
Shelf life Multi-dose – 1 month Single-dose – 3 months Hard capsules are suitable for preparing divided (single-dose) powders in the pharmaceutical industry and pharmaceutical practice. Hard capsules are available in 8 sizes differing in their volume (Figure 1). In pharmacy, only two sizes of capsules are used: capsules with volume 0.67 cm3 (ml) marked as 0 and capsules with volume 0.92 cm3 (ml) marked as 00. In the pharmaceutical industry, there are usually capsules 0 and smaller.
Figure 1: Parts of hard capsule; different sizes of hard capsules To achieve a uniform distribution of drugs in all prepared capsules, it is necessary to fill the whole volume of the capsules bodies. Therefore, the amount of mixture of drug(s) and excipients is not determined by weight, but by the measurement of volume. It is necessary to obtain the mixture volume which corresponds to volume of one used capsule multiplied by 8
the number of prescribed capsules. Very often the amount of mixture of the used drug(s) does not corresponds to the required volume. Therefore, suitable filler must be used for volume adjustment. Lactose, sorbitol, mannitol and microcrystalline cellulose are most often used as fillers. The rheological properties are improved by magnesium stearate and silicon dioxide. Calcium hydrogen phosphate and lactose have antistatic effect.
Divided (single-dose) powders filled into gelatin (HPMC) capsules are prepared as follows: a) Carefully read the prescription. b) Note very carefully whether the drug dose(s) on the prescription is for one hard capsule (marked with abbreviation d.t.d. – give these doses) or for all capsules (marked with abbreviation div. in dos. aeq. - divide evenly into the doses). Check the drug doses according to the pharmacopoeia limits. c) The mixture of substances is prepared in a mortar with rough surface. Before preparation, it is necessary to fill the pores of the mortar bottom with a filler (lactose or special mixture for this purpose) to reduce the loss of drugs. This procedure is absolutely necessary if the potent or highly potent drug is at an amount less than 1 g to all capsules. d) Substances are weighed individually from the smallest to the biggest amount. Add the substance gradually to the mortar and mix powder after each addition. Highly potent drugs are usually used in very small amounts. If the amount of highly potent drugs is less than 0.05 g, the triturated powder drugs are used for preparation due to the more accurate weighing. Trituration is a mixture of drug and inert filler (lactose) at a ratio of 1:10 or 1:100. Before preparation, it is necessary to calculate the amount of trituration corresponding to the amount of prescribed drug. e) After weighing all substances, mix the prepared powder thoroughly again. Within mixing, clean the mortar and pestle with a peeler. f) Move the prepared powder mixture into the cylinder. The cylinder must have a thin layer of lactose or “capsule mixture” on the walls and the bottom (move a small amount of lactose into the cylinder, shake the cylinder in all directions and remove the filler).
9
g) According to the volume of powder mixture, choose a suitable size of capsule. Add the filler to obtain the required volume. After three slight taps, add the filler again. If the volume of drugs is higher than the product of volume of one capsule (0 – 0.67 ml) and the number of prepared capsules, select the capsules with a higher volume (00 – 0.92 ml) and according to this, adjust the mixture volume in the cylinder or add the filler to the volume corresponding to the double number of capsules (in this case, it is necessary to change the dose, e.g. instead of 1 cps, the patient takes 2 cps). h) After volume adjustment, the mixture is weighed to determine the amount of used filler (in grams). i) Return the mixture to the mortar and homogenize it again. The mixture should be sieved if particles agglomerates (grit) are apparent. j) The hard capsules are filled with a prepared mixture. k) How to use the machine for manual capsule filling – Figure 2:
Insert prescribed number of hard capsules into the openings. The screw (4) must be released.
Close the plastic top (2), so the caps of capsules will not fall out when removed from the capsule bodies. The slight pressure of the plastic top ensures the accurate position of capsules in the filling machine.
The screw (4) is fixed to hold the capsule bodies in the plate as the cap holder is removed.
The cap holder (1) is removed using the metal pivots (6). The cap holder takes the caps. The capsules are now opened.
Release the screw which allows for the capsule bodies to completely descend into the plate 3 (3). Align the capsules bodies with the surface of plate 2 (3).
Pour the powder mixture onto plate 2, use the scraper to spread the powder over all capsules.
Fit back the cap holder onto the plate.
Close the capsules with a movement of the cap holder and basic plate (5) against one another.
Remove filled capsules.
10
Figure 2. Scheme of machine for the manual filling of hard capsules
EXAMPLES Exercise 1.1.1 Rp. Natrii hydrogenocarbonatis Magnesii subcarbonatis Carbonis activatis
aa ad 12.0
M. f. pulv. D. S. Swallow 3 x 1 teaspoon for digestive problems Antacid and adsorbent for digestive problem treatment Exercise 1.1.2 Rp. Natrii benzoatis Natrii hydrogenocarbonatis Natrii chloridi Natrii tetraboratis
aa 10.0
Menthae piperitae etherolei
gtt VII
M. f. pulv. D. S. Take the powder on the tip of a knife, dissolve it in a glass of water and gargle 3 times a day. Powder is used for the treatment of nasopharyngeal inflammation as gargle or inhalation. 11
Preparation procedure: First, prepare a powder for gargle as described above without peppermint oil. In the mortar, mix thoroughly a part of the prepared gargle with peppermint oil. Add gradually the rest of the gargle. Finally, mix again thoroughly. Exercise 1.1.3 Rp. Acidi acetylsalicylici
2.5
Paracetamoli
2.0
Coffeini 1.0 M. f. pulv. Div. in dos. aeq. No X (decem) D.S. 3 x 1 capsule Analgesic and antipyretic. Exercise 1.1.4 Rp. Acidi acetylsalicylici 0.3 Coffeini
0.08
Phenobarbitali Codeini phosphatis
aa 0.2
M. f. pulv. D. t. d. No XX (viginti) D. S. 3 x 1 capsule Analgesic
12
Exercise 1.1.5 Rp. Paracetamoli
4.8
Codeini phosphatis
0.5
M. f. pulv. Div. in dos. aeq. No XX (viginti) D.S. 1 capsule against pain Analgesic Exercise 1.1.6 Rp. Atropini sulfatis
0.0003
Phenobarbitali
0.02
M. f. pulv. D. t. d. No XX (viginti) S. 3 x 1 capsule Antispasmodic preparation Exercise 1.1.7 Rp. Belladonnae extracti sicci
0.3
Ergotamini tartratis
0.006
Phenobarbitali
0.4
M. f. pulv. Div. in dos. aeq. No XX (viginti) D.S. 1 capsule against pain Sedative
13
1.2 Dusting powders Dusting powders are locally applied non-toxic and multi-dose (bulk) preparations without systemic action. They can have therapeutic, protective or cover functions. Powders intended for use on open wounds or injured skin must be sterile.
Preparation procedure Dusting powders are prepared in a rough surface mortar with pestle; components must be comminuted, and eventually sieved. They are weighed individually. We start with the substance in the smallest quantity; we then add other substance in order of the quantity required by approximately doubling the portion being mixed with each addition. It is necessary to pass the final preparation through the sieve with suitable opening sizes to ensure that it is grit free and will not mechanically irritate traumatized areas. The excipients used in dusting powders can be inert, but very often they assist in achieving the desired therapeutic effect. They should act as adsorbents, should have a good adhesive capacity and improve the flow properties. Talc and zinc oxide are very often used as excipients. Other excipients are hydrated aluminum silicate; magnesium, titanium, or zinc oxide; calcium, or magnesium carbonate; aluminum, magnesium, or zinc stearate; potato, rice, or corn starch; lactose. The presence of potent and highly potent drugs in dusting powders is not permitted.
Packaging Dusting powders are usually packed into sifter-top containers, powder shakers, plastic containers or wide-neck bottles.
Labelling Red label for external administration, information for patient, others
Shelf life 1 month
14
EXAMPLES Exercise 1.2.1 Rp. Sulphuris
1.0
Acidi salicylici
0.6
Zinci oxidi
14.2
Talci
14.2
M. f. pulv. D. S. Dusting powder Dusting powder for treatment of acne. Exercise 1.2.2 Rp. Tannini
1.5
Acidi salicylici
0.6
Zinci oxidi Talci
aa ad
30.0
M. f. pulv. D. S. Dusting powder Dusting powder for reducing or suppressing perspiration (antihidrotic). Exercise 1.2.3 Rp. Cloroxini
0.6
Zinci oxidi Talci veneti
aa ad
30.0
M. f. pulv. D.S. Dusting powder Dusting powder with antifungal and anti-inflammatory effect. 15
Exercise 1.2.4 Rp. Acidi borici Talci
2.0 ad
20.0
M. f. pulv. D.S. Dusting powder Dusting powder with anti-inflammatory effect. Exercise 1.2.5 Rp. Mentholi
0.1
Camphorae
0.1
Zinci oxidi Talci
aa ad
40.0
M. f. pulv. D. S. Dust on the skin area Dusting powder for treatment of irritated skin. Preparation procedure: First, prepare a mixture of zinc oxide and talc as described above. Divide this mixture into two same parts. In the first smooth mortar, dissolve menthol in small amount of ethanol (1 g) and mix it with half the powder mixture. In the second smooth mortar, dissolve camphora in 1 g of ethanol and mix it with the rest of the mixture. Add the mixture with methol to the powder mixture with camphora and homogenize them thoroughly. During this process, most of ethanol is evaporated and a fine dispersion of methol, camphora, zinc oxide and talc is created.
16
Exercise 1.2.6 Rp. Lithantracis picis
2.0
Zinci oxidi Talci
aa ad
50.0
M.f. pulv. D.S. Dusting powders – aplly on the skin Dusting powder for psoriasis and mycosis treatment. Preparation procedure: The micronized and sieved substances – zinc oxide and talc are weighed and mixed using a mortar and pestle. Then coal tar is weighed into stainless mortar. Dissolve it in at least 10.0 g of ether (approx. in 5 times greater amount than coal tar) and mix it slightly. The dissolution of coal tar in ether and the following steps will be performed in a fume-hood. Then add half amount of powder mixture to the cool tar solution and mix them, clean the mortar and pestle using a scraper during the preparation process. Finally, add the second half of powder and homogenize it to a complete evaporation of ether. At the end, the dusting powder must be uniformly colored. Exercise 1.2.7 Rp. Adipis lanae
2.0
Tritici amyli Talci
aa ad
25.0
M.f. pulv. D.S. Fatty dusting powder – apply on the skin Dermatologic Preparation procedure: The micronized and sieved substances – zinc oxide and wheat starch are weighed and mixed using a mortar and pestle. After this, the wool wax is weighed into stainless mortar and heated under an infrared lamp or over water bath to melt it. Add the mixture of zinc oxide and wheat starch with continuous mixing and cleaning of the the mortar and pestle. 17
1.3 Granules Granules are preparations consisting of solid, dry aggregates of powder particles sufficiently resistant to withstand handling. They are intended for oral administration. Some could be swallowed as such, some are chewed and some should be dissolved or dispersed in water (or another suitable liquid) before being administered. Currently, most of the granulates are prepared as an intermediate product for further processing, such as filling into capsules or compressing into form of tablets. Granules contain one or more active substances with or without excipients and colouring matter and flavouring substances, if necessary. Granules are presented as single-dose or multidose preparations. Each dose of a multidose preparation is administered by means of a device suitable for measuring the quantity prescribed (spoon, knife, scoop, etc.). Each dose is enclosed in an individual container, sachet or a vial for single-dose granules. Several categories of granules may be distinguished:
Effervescent granules (Granula effervescentia) They represent uncoated granules generally containing acid substances (e.g. citric acid) and carbonates or hydrogen carbonates, which react rapidly in the presence of water and release carbon dioxide in the form of bubbles. They are intended to be dissolved or dispersed in water before administration.
Coated granules (Granula obducta) Usually, multidose preparations consist of granules coated with one or more layers of mixtures of various excipients.
Gastro-resistant granules (Granula enterosolventia) To this group belong delayed-release granules that are intended to resist gastric fluid and release the active substance(s) in the intestinal fluid. These properties are achieved by coating the granules with gastro-resistant material (enteric-coated granules) or by other suitable means.
18
Modified-release granules (Granula cum liberatione modificata) They represent coated or uncoated granules which contain specific excipients or which have been prepared by special procedures, or both, designed to modify the rate, the place or the time at which the active substance or substances are released. To this group belong prolonged-release granules and delayed-release granules.
Preparation procedure Granulation (granulates preparation) is the agglomeration process (particle size enlargement) of forming particles (granules) typically having a size range of between 0.2 to 4.0 mm from powder material. In general, it is the process of joining particles together by creating bonds between fine small powder particles. Bonds are usually created by compression or by using a binding agent (binder). The process of granulation is in the pharmaceutical industry widely used with the aim to improve physical properties of materials, such as wettability, flowability, homogeneity, etc because powders of small particle size, irregular shape or surface characteristics are cohesive and do not flow well, but larger and isometric produced granules usually show improved flow properties, bulk density, product appearance, reduced dusting, and prevention of the segregation caused by differences in size or density of the powder mixture components, resulting in improved content uniformity, etc. In the pharmaceutical industry, three basic types of granulation technologies are employed: wet granulation, dry granulation and thermoplastic granulation.
Wet granulation Wet granulation is the process based on adding a liquid solution of wetting agent or binder to fine dry powders. It is one of the most common ways for preparing granulates. The principle of this method is mixing of dry powders with liquid. The used liquid includes solvent, which could be removed by drying. Typical solvents used for granulation include: water (prefered), ethanol, and isopropanol either alone or in combination. The second necessary compound is a binder (povidone, gelatin, cellulose derivatives, etc.), which could be added as dissolved in the previously mentioned wetting liquids or could be in the entry powder mixture present in the dry form and activated in the step of wetting (liquid addition). When the wetting liquid 19
comes into contact with powders (wetting step), binder forms bonds with the powders (agglomeration step), and subsequently the solvent evaporates (drying step). An important step of the process is the adjustment of the formed granulated to desired particle size by sieving (of the wet mass before drying) or milling of the final dried product. The whole described process results in the formation of granules. Granules could be dried in a drying cabinet, fluid-bed dryers, or microwave drier. Wet granulation takes place in a mortar with pestle in a laboratory conditions and in one of two types of closed granulating systems: fluid bed granulators or high-shear mixes in the pharmaceutical industry.
Fluid bed granulation Fluid bed equipment is characterized by a flow of air passing upwards through the bottom screen of the granulator. The binding solution is sprayed above the fluidizing powder bed, in a direction opposite to the air flow (top spraying). Other spraying directions can be used in the same equipment for solids coating or pellets preparation. The granules are created by the adhesion of solid particles to the liquid droplets that hit the fluidizing bed. Partial drying by the fluidizing air occurs continuously during granulation. The process continues until all powder is agglomerated. Complete drying is quickly achieved in the hot air stream when binder spraying is stopped.
Figure 3. Scheme of fluid bed granulation
20
High-shear granulation In the high-shear granulator, an impeller maintains the powder in agitation (movement) in a closed vessel. The binder solution is sprayed from the top. As the liquid droplets disperse in the powder, they form the first nuclei of future granules. The agitation forces produced by impeller and additional chopper prevent the creation of large undesirable agglomerates. However, as mixing and spraying proceed, the existing agglomerates undergo densification, whereby the internalized binder is squeezed out (due to the agitation forces) to the surface of the wet agglomerates. This has two consequences - final agglomerates are harder, and their surfaces are more adhesive, and hence granules growth enters a new, more efficient phase. The process must be stopped in the phase before an excess of liquid or excessive densification provokes a phase inversion, i.e. a slurry forming or uncontrollable growth of agglomerates (‘balling’ phenomenon). The drying step takes usually place after transferring the damp mass into another equipment (fluid bed, cabinet dryer), but the use of single-pot technology (drying in place) has come in use recently. The granules formed in high-shear mixer are denser and show higher mechanical durability than those obtained by fluid bed granulation.
Figure 4. Scheme of high shear granulator
Dry granulation The dry granulation process is used to form granules without using a liquid. This granulation technique is usually used for moisture sensitive drugs. In this process, the primary powder particles are aggregated under high pressure (increasing of material density) which leads to formation of larger clusters, which are subsequently crushed or milled to get granules of the desired particles size. Dry granulation can be conducted under two processes. The first one, by which a conventional tablet presses are used, is called “slugging”. The formed slugs are subsequently broken down to form a granular product, which can then be after sieving and addition of 21
extragranular excipients compressed again to give satisfactory tablets or filled into capsules. The second method uses a roller compactor. The powder is passed between two contrarotating cylindrical rollers to form a cake or a sheet, which are in the next step broken down to a granular product of the desired agglomerates size. The main advantage of this process compared to wet granulation is that solvents for wetting of the powder mixtures and heat for drying are not used. The absence of water is beneficial for substances sensitive to moisture (e.g. aspirin). The absence of organic solvents has a positive impact on the environment and the omission of the drying phase is advantageous for heat sensitive drugs. Granules prepared by this technique disintegrate and dissolve faster than granules prepared by wet granulation, and are slightly hygroscopic.
Melt granulation This method uses the unique property of a specific solid binder to melt after adequate heating and so getting liquid properties. Water and other solvents are not used in this method, which is advantageous for substances sensitive to moisture. The binders used could be different waxes, polymers, and triglycerides with melting point ranging usually from 50 to 80 ˚C. As production facilities are used most often high-shear or fluid bed granulators or cabinet dryers in laboratory conditions. The entire process takes place at elevated temperatures. Agglomerate formation and growth can take place in two ways - distributing of the molten binder to the surface of powder particles, or intrusion of powder particles into drops of molten binder. The advantage of this process are short production times, lower equipment costs, absence of wetting and drying. A certain disadvantages are the risk of degradation of substances sensitive to heat, limited range of possible binders and their higher price.
22
EXAMPLES Preparation of effervescent granulate Excercise 1.3.1 Natrii hydrogenocarbonas
25.5
Acidum tartaricum
12.0
Acidum citricum
10.5
Lactosum
2.0
The individual substances are separately pulverized in a mortar blender. The mixture is heated on a water bath at 80 to 90 °C in a stainless or an enamel mortar blender. The blend is continualy mixed from bottom to up. In order to receive a uniform blend, the mixture can be divided into 2 parts. During the process, the mixture gradually moistens itself by the released crystalline water from the citric acid. When the mixture has the suitable consistency for granulation, it is extruded through a sieve (mesh size 1.25 mm) by pressing using a paper or a plastic card. The extruded granulate is placed onto a suitable plateau (e.g. aluminum foil) which is suitable for drying. The extruded granulate must be dried only in a thin layer. For drying of the whole amount of the mixture about 6 squares of foil should be used. The granulate is dried in a preheated oven (cabinet dryer) at 100-110 °C. To prevent a reaction in which CO2 is released, the drying step must take place very quickly (1-3 minutes). The dried granulate is subsequently dissolved in water at 20 °C to form warm sparkling solution.
Preparation of granulate by the wet granulation Excercise 1.3.2 Lactosum
130.0
Cellulosum microcristallinum
67.5
Povidonum
1.0
Ferri oxidum
1.0
Aqua purificata
60.0
Sieve ferric oxide through a sieve mesh size of 250 microns, weigh it with other ingredients and mix in the high speed granulator (mixer) for 2 minutes. Wet the mixture with 60.0 g of 23
prepared solution of povidone in water at a wetting speed 30.0 g per minute and subsequently extrudate through a sieve with a mesh size of 1.25 mm. Dray the resulting granules in a cabinet dryer at 60 °C for 1 hour. Sieve the dried granulate through a sieve with mesh size 1.00 mm.
Preparation of granulate by the melt granulation Excercise 1.3.3 Lactosum
60.0
Hydroxypropylmethylcellulosum
50.0
Alcohol cetylicus
15.0
Preparation procedure: Sieve the cetyl alcohol through a sieve mesh size 1.00 mm. Mix the mixture of excipients in a Turbula device for 15 minutes. Melt the mixture in a preheated cabinet drier at 80 °C for 10 minutes at the appropriate plateu (eg. baking paper). Finally, pass the mixture through a sieve with mesh size of 1.25 mm. Granules, which include swelling polymers (eg hydroxypropyl methylcellulose) and fatty alcohols (eg. cetyl alcohol) and waxes (eg. montanglycol wax) are used for the preparation of tablets with a controlled drug release.
Preparation of granulate by fluid bed granulation technique Fluid-bed granulation is one of the methods of wet granulation. It uses the properties of fluid (pseudo-fluid) layer, where embedded material is maintained in motion by incoming air stream. Basic part of the used equipment represent the working chamber, which is closed at the bottom by perforated membrane. The upper expansion space is closed by bag filters. The hot air enters the working chamber through the bottom and drives particles against the spray nozzle. The powder mixture is sprayed by granulation liquid (solvent, solution of binder) comming from the nozzle by compressed air. Interparticular bonds are created between powder particles by increasing amount of granulation liquid and granules grow. Wetting liquid evaporates during the drying phase of the proces. Granules prepared by this method are characterized by symmetrical agglomerates and good flowing properties.
24
Excercise 1.3.4 Lactosum Maydis amylum Povidonum Aqua purificata
1300.0 700.0 40.0 500.0
Preparation procedure: Dissolve binder - povidone (Kollidon 25) in distilled water by continual mixing (or by swelling overnight). Insert lactose and starch into working chamber of the fluid bed unit of Multiprocessor MP-1. After completation and closing of the device, heating, granulation and drying of powder mixture follow under conditions listed in the table. Table 2. Conditions of the preparation of granulate using fluid bed granulation technique Conditions Process parameters Heating
Granulation
Drying
Inlet air temperature (oC)
50
40
50
Product temperature (°C)
24
24
30
Air flow (m3/h)
100
100-200
150
Air pressure in the nozzle (kPa)
-
150
-
Spray rate (g/min)
-
30
-
Filter cleaning interval (s)
20
20
20
Duration of phase (min)
10
30
10
1.4 Tablets Tablets (tabulettae, compressi) are solid, oral drugs containing one dose of the drug (drugs) in one tablet. They are intended for oral and peroral administration. They are obtained by pressing dry powder (granulated) mixtures. They usually contain ingredients such as fillers, binders, wetting agents, disintegrants, lubricants, release modifiers of drugs, dyes and corrigents which improve the appearance and taste. There are uncoated tablets (Tabulettae non obductae), film coated tablets, dragees, (Tabulettae obductae), sparkling (Tabulettae effervescentes) for the preparation of solutions, soluble tablets (Tabulettae pro solutione), for the preparation of dispersion (Tabulettae pro
25
dispersione), with controlled release (Tabulettae cum liberatione modificata), enteric (Tabulettae enterosolventes), and acting in the oral cavity (Tabulettae orales). Uncoated and coated tablets are taken orally: uncoated tablets can be disintegrated in a small amount of water before ingurgitation. Coated tablets should be swallowed whole. Chewable tablets (compress manducabiles) contain disintegrants, they do not disintegrate, but slowly dissolve. They are contained in the stomach and intestinal tract as absorbable substances and because of this they should be swallowed after chewing. Chewing pills and tablets that dissolve in the mouth contain locally acting drugs. In similar way dissolving buccal and sublingual tablets are a convenient form for systemically acting drugs, which are not resistant to the aggressive environment of the stomach. The drug which is applied by this method is not much influenced by the first pass effect. The formulation of tablets is determined with certain aims. Most important are: appropriate mechanic resistance, good content uniformity of drug and adequate drug release. A prerequisite for obtaining mechanically resistant tablets is the sufficiently plastic deformability of the tablet mass. Fragile and also highly elastic materials are not suitable for tableting. Fragile substances usually can´t be pressed in tablets that are hard enough. Tablets, which are compressed from highly elastic materials disintegrate poorly. During pressing, two types of binding forces are formed: adhesive resp. cohesive forces and solid bridges created from the binders. Tablets, where cohesion is based on cohesion and adhesion, are easy to disintegrate. In the presence of solid bridges (bridges formed by binders), disintegration is limited and tablets dissolve slowly. The tablet mass (a mixture of drugs and excipients or granules and excipients) should have good flowability, humidity, particle size distribution, and compressibility to ensure accurate dosing and ease molding. Therefore, the production of tablets is impossible without excipients. These are: Fillers: (see chapter about granulates) Binders: most important are the water soluble vinyl polymers as povidon, polyvinyl alcohol and cellulose derivates as hypromellose, hyprollose, polysaccharides as starch and its physical modifications (pregelatinized starch), dextran, dextrin, only rarely guar gum, alginates, etc. Disintegrants: There are two groups: 1. Swelling disintegrant: various kinds of starch and its chemical and physical derivates (pregelatinized starch or carbamoylpectin), crosslinked 26
polymers such as crosscarmellose, crosspovidon. 2. capillary disintegrants: cellulose and microcrystalline cellulose. Anti-adherents: (lubricants and anti-adhesives): magnesium, calcium, or aluminum stearate, talc, colloidal silicon dioxide, and lauryl sulphate. Fillers, binders and sometimes disintegrants are the internal (intragranular) phase and their mixture may be granulated together. Disintegrant and lubricants are external (extragranular phase) which is added to the granulate. The tablets are obtained by pressing on the rotary and eccentric presses. Eccentric presses are now replaced by the rotary presses in almost every area and are used only in some hospital pharmacies or in the beginning steps of pharmaceutical development. Pressing is performed in three steps: 1. Lower punch is vertically removed down from the matrix and the space in the matrix is filled with the tablet blend by the horizontally moving of hopper. 2. Upper punch descends into the matrix and the hopper is horizontally removed. Lower stamp does not change position and the upper punch is continually pressing the blend in the space in the matrix. 3. Upper punch is continually going up from the matrix and the tablet is removed by the lower punch from the matrix. The hopper goes back to step 1. During the filling of the matrix with the blend, the lower punch is going down from the matrix and the hopper shunts tablet from the space of pressing. When we start to work with the eccentric press, the adjustment of the correct weight of the tablet is necessary. This adjustment is performed by moving the lower punch into the matrix. The hardness of the tablets is directly influenced by the pressing force during the tableting process. The pressing force resp. the tablet hardness is enhanced by the extensity of immersion of the upper punch to the matrix (see step 2). Before starting the pressing process, it is first necessary to press a few tablets manually by turning the wheel that moves the punches. The indicative pressed tablets are tested for correct weigh and hardness. During the pressing sample of the indicative tablets, the wheel can be easily turned manually. If not, the pressing force should be reduced. If any complications appear during the pressing process, the tablet press must be stopped immediately. 27
EXAMPLES Preparation of tablets from granules Excercise 1.4.1 Ad 0.5 g of talc to the granules, which are prepared according to the procedure described in Exercises 1.3.2 and homogenize in Turbula for 5 mins. Put the blend into the hopper of the eccentric press. The lens-shaped tablets with a mass of 70 mg, are pressed onto an eccentric press using punches with a diameter of 5 mm. Check the finished tablets for weight uniformity, hardness, friability and disintegration in accordance with the procedures specified in Chapter 3. Excercise 1.4.2 Add 67.6 g of microcrystalline cellulose and 0.5 g of magnesium stearate to the granules, which are prepared according to the procedure described in Exercise 1.3.2. Homogenize the mixture in Turbula for 5 mins. Place the blend into the hopper of the eccentric press. Flat tablets with the weight of 200 mg and a diameter of 10 mm are pressed. Check the finished tablets for weight uniformity, hardness, friability and disintegration in accordance with the procedures specified in Chapter 3.Excercise 1.4.3 Acidum acetylsalicylicum
40.0
Pulvis granulatus simplex
159.0
Magnesii stearas
1.0
Preparation procedure: Mix the weighed quantity of acetylsalicylic acid with the "granulatum simplex" prepared according to Exercise 1.2.2. Add a lubricant to the mixture and homogenize for 5 minutes in Turbula. Flat tablets with a weight of 500 mg and a diameter of 10 mm are pressed on the eccentric press. Check the finished tablets for content uniformity according to article 2.9.40 Ph.Eur.
28
Determination of acetylsalicylic acid (ASA) Excercise. 1.4.4 Weigh each tablet accurately and then dissolve it in a flask with a ground stopper in 10 ml of alcohol 96%. 20.0 ml of NaOH with a concentration of 0.1 mol/l is added. Close the flask and allowe to stand for 1 h. Then add 0.2 ml of phenolphthalein as an indicator and titrate with standard hydrochloric acid 0.1 mol/1. The blank is performed. 1 ml of NaOH (0.1 mol/l) and corresponds to 9.008 mg of ASA.
Preparation of tablets by direct compression Excercise. 1.4.5 Monitoring the effect of disintegrants on the disintegration of tablets Blend No 1. Lactosum monohydricum
100.0
Cellulosum microcristallinum
97.0
Povidonum
1.0
Magnesii stearas
2.0
Blend No 2. Lactosum monohydricum
85.0
Cellulosum microcristallinum
97.0
Povidonum
1.0
Amylum tritici
15.0
Magnesii stearas
2.0
Blend No 3. Lactosum monohydricum
70.0
Cellulosum microcristallinum
97.0
Povidonum
1.0
Amylum tritici
30.0
Magnesii stearas
2.0
Preparation procedure: Weigh and mix the individual components in the Turbula for 10 minutes. Flat tablets with a weight of 200 mg and a diameter of 10 mm are pressed on the 29
eccentric press. The hardness is adjusted at 50 kN. This procedure is the same for blends 1, 2 a 3. Tablets are tested on disintegration time according to the procedure described in Chapter 3. Excercise. 1.4.6 Monitoring the influence of fillers on flow characteristics and mechanical properties of the blends. Blend No 1. Calcii hydrogenophosphas dihydricus
100.0
Cellulosum microcristallinum
97.0
Povidonum
1.0
Magnesii stearas
2.0
Blend No 2. Calcii hydrogenophosphas dihydricus
130.0
Cellulosum microcristallinum
67.0
Povidonum
1.0
Magnesii stearas
2.0
Blend No 3. Calcii hydrogenophosphas dihydricus
160.0
Cellulosum microcristallinum
37.0
Povidonum
1.0
Magnesii stearas
2.0
Preparation procedure: Weigh the individual components and mix for 10 minutes in Turbula. Flat tablets with a weight of 200 mg and a diameter of 10 mm are pressed on the eccentric press. This procedure is the same for blends 1, 2 a 3. Blends are tested on flowability (Ph.Eur.) and tablets are tested on hardness and friability (Ph.Eur.). Excercise 1.4.7 The blend, which is prepared according to Exercise 1.4.5, is placed into the hopper of the eccentric press. Tablet-shaped lens with a mass of 200 mg are pressed using punches with a diameter of 10 mm. The finished tablets are checked for hardness according to Ph.Eur.
30
Preparation of effervescent tablets by direct compression Excercise. 1.4.8 Lactosum
50.0
Calcii hydrogenophosphas
45.0
Acidum citricum
50.0
Natrii hydrogenocarbonas
50.0
Magnesii stearas
5.0
Preparation procedure: Micronize the citric acid in mortar blender and sieve sodium hydrogen carbonate through a sieve with a 0.5 mm mesh. Mix lactose, calcium phosphate for direct compression (Parmcompress, Emcompress, or DiCafos), citric acid and sodium hydrogen carbonate in the Turbula for 10 min. Add magnesium stearate and then mix for 5 min more. Flat tablets with a mass of 500 mg are pressed using punches with a diameter of 10 mm. Check the finished tablets for disintegration according to the procedures in Chapter 3.Excercise 1.4.9 Dissolution test Dissolution test will be performed with OTC tablets containing magnesium gluconate. Test procedure: Dissolution testing is carried out according to an article "The dissolution testing" in chapter 3 with 6 tablets. The dissolution medium is 1000 ml of purified water. The sample of 100 ml, after being 45 min in the dissolution, is transferred from the dissolution bottle into a 250 ml flask and diluted by purified water to 200 ml. Add to this flask 10.0 ml of ammonium chloride buffer solution with pH 10.0 and about 50 mg of eriochrome black with sodium chloride. Heat it to 40 °C and titrate with a standard solution of sodium edetate 0.02 mol/l from the violet blue color to the deep blue color. 1 ml of standard solution of disodium edetate 0.02 mol/l corresponds to 0.4862 mg Mg.
1.5 Coated tablets Coated tablets (Tabulettae obductae) are tablets covered with one or more layers of mixtures of substances such as natural or synthetic resins, polymers, gums, fillers, sugars, plasticizers, polyols, waxes, colouring matters, flavouring substances and sometimes also active ingredients. They are single-dose preparations intended for oral administration. A broken section, when magnified, shows a core which is surrounded by a continuous layer of a 31
different texture. The tablets may be coated for a variety of reasons such as to protect the active ingredients from air, moisture or light, the masking of unpleasant tastes and odours or for the improvement of appearance. The substance used for coating is usually applied as a solution or suspension. The coated tablet in the gastrointestinal fluid should liberate the drug. The drug may be liberated from the disintegrated tablet or by permeation through a coating level. Three main categories of coated tablet may be distinguished: sugar-coated (dragees), filmcoated, and some modified-release tablets (e.g. enteric coated tablets with delayed release).
1.5.1 Dragees (sugar coated tablets) Dragees are coated tablets produced preferably in coating drums. The coating level is, during production, created from fillers like: sucrose, starch, calcium carbonate, calcium sulfate, talc, etc., and solutions of binders like: starch syrup, sucrose, gelatin, arabic gum, cellulose derivatives and solutions of povidone. Furthermore, there are dyes, polishing and moisture protective agents. Dragees are the oldest obductets but still frequently used. It consists of five phases: Sealing: this is necessary to protect the tablet core against moisture from the solution of sucrose. Sealing also prevents migration of some raw materials or drugs from tablet to coating level. A moisture protective film is built up using materials such as: shellac, cellulose esters, zein etc. Subcoating: prior to applying the coating, it is necessary to round the edges of the core. At this stage, care must be taken to ensure that the deposited layer is regular and well-dried. The cover layer allows regular rotation cores. Smoothing: the product should not be, by the end of subcoating, too rough to continue with colour coating. Smoothing is usually achieved by applications of clean saccharose syrup. These are applied in about 7 – 8 layers. Each layer should be applied after drying the previous layer. Colour coating: during this operation, the coating dispersion of saccharose syrup contains the colour solids necessary to achieve the desired shade. Water-insoluble pigments are used including the aluminium lakes of the water-soluble colours. The product is dried by hot air. 32
Polishing: the principle of polishing is the formation of a hydrophobic layer, which improves the appearance and also has a protective function. Dragees are polished with beeswax or carnauba wax, mineral oil which are added either in the form of powder, solution, emulsions or suspension. Polishing is also a protection against moisture. Dragees are produced either by applying an alternating wetting agent and a filler or by coating the cores with the suspensions of fillers in a wetting agent. During the procedure, it is necessary to initially adjust the surface of the drum so that the core does not slide over it. For the uniform application of the coating, it is important to have rotational movement cores, which contribute to the roughening of the surface of the drum. The inner surface of the drum is first wiped with a solution or hydrogel binder, such as 4% carboxymethyl cellulose hydrogel and the wet layer is dusted with talc or powdered sucrose during the simultaneous rotation of the drum. The modified surface is dried.
EXAMPLES Coating by a solution of coating material Exercise 1.5.1.1 300 g of cores, prepared in task 1.4.1., are inserted into a modified coated drum and left there for about 5 min. to rotate. Tablets are removed and dedusted on the sieve. The edges are abraded during this operation. The cores are given back into the drum, the speed of rotation and pan inclination is adjusted for optimal rotation of cores. The lacquered insulating layer is applied to the cores, which may consist of hydroxypropyl methylcellulose E - type in aqueous or alcoholic solution. Only after the isolation of cores may the application of the individual layers be started. Filler No. 1 Saccharosum
25.0
Talcum
25.0
Calcii carbonas
34.0
Silica colloidalis anhydrica
16.0
Preparation procedure: Mix the powdered sucrose, talc, calcium carbonate and colloidal anhydrous silica (Aerosil 200) and sieve it through mesh 0.50 mm. 33
Filler No. 2 Saccharosum
70.0
Talcum
20.0
Solani amylum
10.0
Filler No. 3 Calcii carbonas
50.0
Talcum
50.0
Fillers 2 and 3 are prepared in the same manner as a filler No. 1 Excercise of binder solution: Gelatina
1.5
Saccharosum
60.0
Aqua purificata
38.5
Preparation procedure: 10% solution of gelatine in water is prepared so that the gelatin is left to swell in water for 15 min and after that the mixture is heated. Dissolve the sucrose in the remaining amount of purified water. Mix both solutions and filter it if necessary. This solution is applied warm at temperature of 50-60 oC. Once the cores begin to stick to the wall of the drum and to each other, add the filler, so that the cores start again to move freely because the filler absorbs the moisture. The applied layer is dried with hot air. Apply the additional layers to the dried cores. If the cores have the prescribed weight, they may be smoothed with an application of a simple syrup and dried without the addition of hot air. The pigment can be added to the syrup and the degree of smoothing may be combined with coloring. Polishing of cores is carried out with 1-2 ml solution of the polishing agent at a slow speed of the drum. The polishing solution may be a 5% solution of white wax in hot ethanol 96% or polishing emulsion (paste). Dragees are allowed to dry at room temperature in a suitable place for 24 hours. Disintegration and weight uniformity tests are performed. Yield is determined.
34
Coating by filler and binder in suspension Exercise 1.5.1.2 Gelatinae solutio 10%
150.0
Sirupus simplex
800.0
Talcum
25.0
Titanii dioxidum
5.0
Solani amylum
100.0
Silica colloidalis anhydrica
20.0
Preparation procedure: The gelatin solution is prepared in the same manner as No 1.4.1 and mixed with syrup. Sieve solid powdered ingredients through a mesh of 0.25 mm and add in small portions while stirring. The suspension was homogenized in a mixer. 300 g of cores is coated with an insulating layer in the same manner as in task 1.4.1. The application of the warm suspension (50-60 °C) is carried out at a high rotational speed and a large angle of inclination of the coated drum. The suspension is applied in a thin stream to all cores so that they are uniformly wetted. Additional layers are applied after drying the previous layer. Disintegration and weight uniformity tests are performed. Yield is determined.
1.5.2 Film coated tablets In the manufacture of film coated tablets, modified drums are primarily used, sometimes also fluid bed apparatus. The coating layer is much thinner than dragees and is made up of filmforming substances, mostly cellulose derivatives and polyacrylates. Film-forming substances are applied to the cores in drum coaters or in fluid bed coaters in the form of an aqueous solution or an aqueous dispersion by using a spraying nozzle. Because of legal restrictions, organic solvents are rarely used. Coating liquids are composed of a film forming agent and plasticisers which increase the flexibility and strength of the formed film, e.g., macrogol, castor oil, phthalates, triethyl citrate etc, anti-sticking agents, e.g., talc, and colorants. Film-coating is performed with laboratory apparatus with a Wurster column. A diagram of the working chamber is shown.
35
Figure 5. Schema of the working chamber fluidized bed facility with a Wurster column Exercise č. 1.5.2.1 Hydroxypropylmethylcellulosum
5.0
Methylrosanilinii chloridum
0.05
Aqua purificata Preparation
procedure:
ad Dissolve
50.0
hydroxypropyl
methylcellulose
(Pharmacoat)
in
o
approximately 20 g of purified water heated to about 80 C. Add the remaining water (room temperature) to the solution and during stirring cool it down. Add the dye to the solution for dissolving. Place 100 g of lens-shaped tablets with a diameter of 5 mm into the working fluid chamber apparatus Wurster type M-100. Spraying is performed according to the below mentioned instructions: Test on microscopical integrity of cores and yield are performed.
36
Table 3. Conditions of coating by water solution Process parameters
Conditions Heating
Spraying
Drying
Inlet air temperature (oC)
50
50
50
Air press in nozzle (kPa)
-
80
-
Spray rate (g/min)
-
1-4
-
Time of operation (min)
5
cca 60
5
Microscopical integrity of cores and yield are performed. Exercise č. 1.5.2.2 Ethylcellulosum
1.3
Acidum stearicum
4.0
Ethanolum 96 %
q.s.
Preparation procedure: Dissolve ethyl cellulose in a small portions at approximately 20 fold amount of 96% ethanol under stirring and heating in a water bath (40-50 °C). After dissolving ethyl cellulose, dissolve the stearic acid (it is more soluble in ethanol). The dispersion was allowed to cool. On the 100 g of lens shaped cores, ethanolic solution of ethyl cellulose and stearic acid is applied under the conditions listed in the Table 4. The quantity of the coated layer is performed. Measurement is repeated three times.Table 4. Conditions of coating with organic solution Process parameters
Conditions Heating
Spraying
Drying
Inlet air temperature (oC)
up to 40
up to 40
up to 40
Air press in nozzle (kPa)
-
80
-
Spray rate (g/min)
-
1-2
-
Time of operation (min)
5
Depends on dispersion volume
5
37
1.6
Oral solid dosage forms with controlled release
Oral solid forms with controlled release formulations are produced using special additives or procedures which modify the rate of release and absorption of drugs in the gastrointestinal tract. They can be divided into matrix tablets, coated tablets and drug microforms. Matrix tablets, according to the used carrier excipients, are distinguished from the hydrophilic matrix tablets, fat matrix and insoluble matrix (skeletal tablets). The oral drug microforms are pellets and microcapsules. The formulation of sustained release formulations is restricted by the dose of the drug, its water solubility, time and large therapeutic effect, and other factors dependent on the form and manner of processing. As excipients are used substances retarding the dissolution rate of the drug: insoluble polymers based on derivatives of acrylic and methacrylic acid, swellable polymers based on cellulose derivatives and fatty and waxy substances.
1.6.1 Matrix tablets The hydrophilic matrix systems are based on swellable polymers which, in contact with aqueous solutions, start hydration and the dissolution of the polymer. After wetting the surface of the molded polymer, it begins to partially hydrate and form a gel layer. During this initial phase, there is a releasing of the initial dose of the dissolved drug from the matrix surface. This part of the drug causes the first therapeutic concentration in plasma. The formation of a gel barrier on the basis of hydration is the first essential step in achieving a controlled release of the drug from the dosage form. The protective gel layer allows water to penetrate into the tablet continuously. The solvent enhances the mobility of the polymer chains and leads to their loosening and transformation into a swollen gel. The initial gel barrier melts and is replaced with a new layer, which must be sufficiently strong to allow slow diffusion and prolong the drug release. Gel consistency is dependent on the viscosity, polymer concentration, and its chemical structure. The result is an almost linear reduction of the tablet diameter, which also contributes to the erosion of the polymer. Drug release from these systems is performed dependent on the solubility of the drug in an aqueous medium by diffusion (prevalent in soluble drugs), erosion (predominance of poorly soluble drugs), and in combination with both depending on the drug solubility and relaxation of the polymer chains. 38
The most common polymers used for the hydrophilic gel matrix are cellulose derivatives: hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose - nonionic polymers, and sodium carboxymethyl cellulose - ionic polymer. As other polymeric materials, modified starches, modified polymeric carbohydrates, alginates, povidone, polyethylene glycols and others may be used. Their use in comparison with the cellulose derivatives is very small. Hydroxypropyl methylcellulose (HPMC) is known under the trade name Methocel ® or Pharmacoat®. On the basis of their characteristics, such as degree of substitution, the ratio of the methoxyl and hydroxypropyl groups, the degree of polymerization and the resulting molecular weight and viscosity there are three groups designated E, F and K. For the matrix tablets, type K is the most suitable, which quickly hydrates. The release rate of the drug affects the viscosity of the polymer, its concentration, the solubility of the drug, and other added excipients or the interaction of the drug with the polymer (most complex formation). The dissolution profiles of the drugs produced by direct compression or wet granulation did not show any significant differences in the rate of drug release. But a uniform distribution of the polymer in each of the thus prepared matrix is necessary. The coating of the matrix leads to a reduction in the rate of hydration of the polymer: the drug is released slowly from the obductet rather than from the uncoated core and its effect is slow.
EXAMPLES Preparation of matrix tablets I by direct compression Exercise č. 1.6.1.1 Diltiazemi hydrochloridum
50.0
Lactosum monohydricum
49.0
Hydroxypropylmethylcellulosum
100.0
Magnesii stearas
1.0
Preparation procedure: Mix the drug with lactose, hydroxypropyl methylcellulose type K4M CR type and magnesium stearate in a Turbula for 15 minutes. Tablets weighing 200 mg were compressed on a Korsch eccentric tabletting press using flat punches with a diameter of 10 mm.
39
Preparation of matrix tablets II by direct compression Exercise 1.6.1.2 Diltiazemi hydrochloridum
50.0
Cellulosum microcristallinum
49.0
Hydroxypropylmethylcellulosum
100.0
Magnesii stearas
1.0
Preparation procedure: Mix the drug with with microcrystalline cellulose, hydroxypropyl methylcellulose type K100M CR and magnesium stearate in a Turbula for 15 minutes. Tablets weighing 200 mg were compressed on a Korsch eccentric tabletting press using flat punches with a diameter of 10 mm.
Preparation of matrix tablet by melt granulation Exercise Exercise 1.6.1.3 Add 2.5% of magnesium stearate and 0.5% of Aerosil to the 200 g of the granulate prepared in the role of Exercise 1. 2. 10, and mix it in a Turbula for 10 minutes. Tablets weighing 200 mg were compressed on a Korsch eccentric tabletting press using flat punches of 10 mm diameter. The prepared tablets are tested on hardness and friability according to the procedures specified in Chapter 3.
1.6.2 Pellets Pellets are in the pharmaceutical industry defined as small, free-flowing spherical or semispherical particles manufactured by the appropriate agglomeration technique from the powdered mixture of active substances and excipients. They are intended for further processing to multiple dosage forms (especially for filling into hard capsules or compression into tablets). Their size is usually in the range of 0.5 to 1.5 mm in diameter. Currently, the pharmaceutical production of pellets is primarily focused on preparing pellet oral dosage forms with controlled drug release, which may be gastro-resistant or may have the ability to slow down the drug release or to specify the place of action. For this purposes, pellets can be coated or have a matrix structure.
40
Coated pellets Drug release from this type of pellets is controlled by the polymeric coating layer. Pellets are formulated from inactive (non-pareil) cores usually from sucrose, starch or microcrystalline cellulose, in most cases, on which the layers of active ingredient, and finally the coating release control layer are applied.
Matrix pellets Matrix system represents a heterogeneous solid particles dispersion of the active substance in release modifying matrix. It is the simpliest approach to the preparation of dosage forms with modified release of drugs. Technological advantages of pellets:
High flexibility in the design and development of dosage forms containing pellets, especially due to the possibility of combinations of several types of pellets in one final dosage form (tablet, capsule)
Improved drug stability
Visual attractiveness of these formulations (preparing pellets of different colours)
Optimal shape for coating
Modified drug release
Therapeutical advantages of pellets:
Minimum irritation of the gastrointestinal tract (GIT), since after oral administration, pellets, form an uniform dispersion in GIT due to the peristaltic movements, Their GIT passage is independent on gastric emptying, and thereby create a lower local concentration of the dissolved drug and reduce the irritation of the GIT in contrast to maximized absorption
Modified-release pellets reduce fluctuations in plasma drug levels and thus reduce side effects and prolong the effectiveness of treatment dependent on sufficient levels of the active substance in the systemic circulation
41
Simplifying the dosing schedule and thereby improving patient compliance
There are also some disadvantages associated with the technology of preparation of pellet formulations, to which belong mainly high costs and the time consumption of this process, associated with the purchase of development or manufacturing equipment, personnel training, optimization and validation of the process, as well as the inability to use all materials in this procedure.
Preparation procedures used for pellet´s production There are several categories of pelletization technologies. The selection depends on the state in which the active substance is (solid form, solution, suspension) and on the nature and properties of excipients. The used pelletization technique greatly influences the physicalchemical properties of the final product, which is reflected in the most important criterion of pellets, in a dissolution profile (drug release rate). Agglomeration by motion: Spherical agglomeration or balling Rotoagglomeration Agglomeration by press: Compressing Extrusion and spheronization Agglomeration by layering: Layering of solution, suspension, powder on inactive cores Spray agglomeration: Spray drying
Spray cooling (congealing)
AGGLOMERATION BY MOTION It is a process in which fine powder material, is transformed into spherical particles of larger size by constant motion, after a suitable wetting. 42
Spherical agglomeration/balling is in practice the less used pelletization process, using principle of wet agglomeration of the fine particles in a motion in the dragee drum. Cores are formed at the beginning of the process, with growth in the second phase. More advanced and more modern method of preparation of pellets is rotoagglomeration technology. This method, despite the high cost of the manufacturing equipment, provides a number of advantages, including: flexible manufacturing, easy automatization of the manufacturing process, and the ability to measure and control the production variables, the complete preparation cycle occurs in one closed system. Rotoprocessors (Niro-Aeromatic), or the rotation granulators (Glatt) are devices combining the properties of fluidized-bed equipment and spheronizer. In these devices 3 forces cause the formation of pellets from the entry powder materials – centrifugal, gravitational and fluidized force. Centrifugal force, created by a rotating disk, drives particles to the walls of the working chamber. Around the edge of the rotating disk flows the air stream which lifts particles to float vertically. In the upper part of the working chamber this force weakens and the gravitational force starts to predominate, and particles fall back to the surface of the rotating disk. The combination of these three forces creates a special kind of movement of the material into which the nozzle is positioned tangentially and sprays the binding dispersion.
Preparation of pellets using rotoagglomeration technique Excercise 1.6.2.1 The process of preparing pellets by rotoagglomeration in the rotoprocessor Aeromatic MP-1 can be divided into four parts. In the first phase (wetting phase), the mixture of powdered excipients, or excipients and drugs is wetted in the working chamber of the rotoprocessor unit by spraying. As wetting liquid water or aqueous solutions of binders can be used. Rotoprocessor is not suitable for homogenization of powdered ingredients, because it cannot achieve homogenous mixing. Therefore, it is necessary to prepare a powder mixture in a homogenizing device (high-speed mixers, planetary mixers, sigma blenders, etc.). The amount and composition of the powder mixture, speed of the rotating plate, the wetting speed and the total amount of the added wetting liquid are the main variables affecting the formation of pellets in this phase. Other variables of less importance for the formation of pellets are air pressure in the spray nozzle, 43
the air pressure in the gap between the rotating plate and the inner wall of the working chamber and temperature. In the second phase, the wetted mixture is spheronized on a high speed rotating plate. In this phase the rotation speed has a major influence on the final product and the time of spheronization. Other variables are temperature and air pressure in the gap between the rotating plate and the inner wall of the working chamber. In the third phase, the pellets are dried. The inner part of the rotoprocessor is lifted, the pellets get between the inner and outer wall of the equipment where the hot air floats, dry and afterwards fall back into the inner part of rotoprocessor. The whole process is repeated until the pellets are completely dry. The last phase of the whole process is the cooling of the final product. Pellets are held in the same motion as in the drying phase, but at low temperature. At the end of this phase the final pellets are removed from the rotoprocessor unit. Table 5. Preparation procedure: Composition of powder mixture (g): Microcrystalline cellulose (Avicel PH 101) 350.0 Lactose 200 mesh
650.0
Homogenization: Stephan UMC 5:
5 min, 1500 rpm
Wetting liquid (purified water)
440.0
Inlet air temperature:
30 °C
Product temperature:
30 °C
Air flow:
100 m3/hour
Air pressure in the gap between the rotating plate and the inner wall:
100 kPa (1.0 bar)
Speed of rotating plate:
0 - 1000 (= 0 - 2000 rpm)
Air pressure in spraying nozzle:
80 kPa (0,8 bar)
Spray rate:
30 g/min
44
Wetted mixture is spheronized by the following condition: Inlet air temperature:
30 °C
Product temperature:
30 °C
Air flow:
100 m3/hour
Air pressure in the gap between the rotating plate and the inner wall:
200 kPa (2,0 bar)
Speed of rotating plate:
900 (= 1800 rpm)
Spheronization time:
2 min
Pellets are dried by the following conditions: Inlet air temperature:
80 °C
Product temperature:
50 °C
Air flow:
470 m3/hour
Air pressure in the gap between the rotating plate and the inner wall:
200 kpa (2.0 bar)
Speed of rotating plate:
300 (= 600 rpm)
Pellets are cooled in the following conditions Inlet air temperature:
20 °C
product temperature:
40 °C
Air flow:
470 m3/hour
Air pressure in the gap between the rotating plate and the inner wall:
200 kpa (2.0 bar)
Speed of rotating plate:
300 (= 600 rpm)
The produced pellets are evaluated for overall yield, particle size distribution by sieve analysis, friability, shape and density (see Chapter 3. Quality evaluation methods).
AGGLOMERATION BY PRESS These methods are based on the principle of compressing the drug and excipients by mechanical force to form pellets. The first process is simple compression in which pellets, looking like small tablets of spherical shape are produced. The second procedure is extrusion and spheronization, which is based on the principle of extruding the wet plastic mass through a perforated die of extruder and subsequent rounding (spheronizing) of the cylindrical semi-product into the form of spherical pellets in a spheronizer.
45
Preparation of pellets using extrusion and spheronization One of the most widely used methods for the preparation of pellets for pharmaceutical purposes, especially with a high content of active ingredients is extrusion and spheronization. Extrusion/spheronization is an interconnected multi-stage process consisting of five interdependent technological operations. The process begins with the homogenization of dry drugs and excipients, followed by wetting the powder mixture, thereby converting into the form the plastic mass (similar to wet granulation), suitable for extrusion into long cylinders, which are then transformed in the spheronizer into pellets of spherical shape. The final step is drying the product. Homogenization and wetting The initial step in the preparation of pellets using extrusion/spheronization is thorough mixing the powders in suitable equipment, followed by wetting of the material. The most common wetting liquids used are water and ethanol. If there is a low moisture level inside the wetted mass an excessive pressure and friction emerge in the extruder leading to large proportion of dusty material. Oval bodies and double-pellets are produced in the spheronization step, due to a lack of plasticity of extrudates. On the other hand the excess of liquid in the material causes its sticking to the walls of the spheronizer, and particle agglomerates in a wide range of sizes are created. The amount of required wetting liquid is affected by the solubility of the used ingredients in the wetting liquid. The dissolution of soluble drugs or excipients increases the volume of the liquid phase, which can lead to an over-wetted system, compared with the mixture of insoluble drugs and excipients. In general, we can conclude that substances with a lower solubility require a higher proportion of wetting liquid. Extrusion The second step in the production of pellets is extrusion, whose principle lies in the movement of plastic mass through a perforated extrusion die by pressure to form cylinders 2 to 20 cm long. The resulting extrudate should be hard enough, should have a smooth surface and should not be sticky to ensure non problematic next processing. Selection of a suitable extruder for the entire production process is a very important criterion, because different types differ both structurally and in the operating principles. In the pharmaceutical industry, screw extruders are used usually, allowing for the continuous extrusion process. In this type of extruder, the wet material is fed through a hopper to the screw which transports it through the 46
supply area to the pressure field, in which compression occurs, and where it is then forced through the extrusion die. According to the position of the extrusion die to the axis of the rotating screw, extruders can be divided into two types: radial – extrusion die is located around a horizontal axis of the screw, axial – extrusion die is placed perpendicular to the axis. Spheronization During the spheronization step, the extrudate is broken due to the effects of the rotational motion and centrifugal force of the rotating plate into smaller rod-shaped particles that are then moulded into a spherical final product - pellets. The spheronizer consists of an open top, vertically positioned cylinder with smooth inner walls, whose diameter ranges from 20 cm (lab) to 100 cm (industrial). At the bottom of the cylinder is placed a rotating plate (rotating disk) with serrated surface, whose edge is 0.25 mm away from the inner cylinder wall. The surface of the disc increases the frictional force necessary to form spherical pellets. The process of spheronization can be divided into three basic steps: 1) breaking of cylindrical extrudated particles, 2) agglomeration of segments, 3) smoothing of the final particles. The spheronization process is significantly influenced by factors such as: the speed of rotation of the spheronization plate, the amount of inserted extrudate and spheronization time. For the formation of spherical pellets it is necessary to find an appropriate balance between these three variables. When a small amount of extrudate is inserted into the spheronizer no interactions between particles are created, while large quantities of material reduce the interaction of particles and the serrated plate. The speed and time of spheronization have a significant effect on the properties of pellets, such as: distribution of particles size, their shape, flow and mechanical properties. A higher speed of spheronization results in the creation of pellets with improved mechanical and flow properties, while lower speeds may cause an insufficient rounding of the particles. Extension time of spheronization leads to the formation of particles with better sphericity, but the process becomes less economical. It has been shown experimentally that the most suitable speed of rotation of the plate is 200-2000 rpm and an optimal time of spheronization is usually 2 to 15 minutes. Drying In the process of the production of pellets by extrusion/spheronization method, there is incorporated a relatively large amount of water to the material. Pellets after spheronization contain a significant percentage of residual moisture and therefore drying is necessary. This 47
process has a strong influence on the final product structure (density, size, hardness). There are several methods and equipment used to dry the pellets, such as: drying at room temperature, in a hot air oven (cabinet dryer), a microwave oven or in a fluid-bed device using different temperatures. Excercise 1.6.2.2 Preparation procedure Composition of powder mixture (g): Microcrystalline cellulose (Avicel PH 101)
200.0 g
Purified water
220.0 g
Preparation procedure: 1. Homogenization and wetting: Weight 200 g of Avicel PH 101. Put this powder into a mixer and add 220 g of water by stirring. 2. Extrusion: Put the wetted mass into the hopper of extruder. Prepare the extrudate with 1 screw extruder (speed 100 rpm) with an axial position of extrusion die with pores diameters of 1.25 mm. 3. Spheronization: Put extrudate into spheronizer with serrated rotating plate with diameter of 23 cm. Spheronize the material for 10 min by 1000 rpm. 4. Drying: Dry pellets in hot air oven by 60 °C for 8 hours. 5. Evaluation: Evaluate physico-mechanical and flow properties of the final pellets.
AGGLOMERATION BY LAYERING This process is based om processing the inactive cores, on which the suspension, solution or powder of the active substance is applied with a spray nozzle. The applied layer is dried with hot air and the whole process can be repeated until the desired active layer or particle size is formed.
Preparation of pellets by layering the active substance on inactive cores Excercise 1.6.2.3 This process runs in a laboratory fluid-bed unit and consists of 3 steps.
48
Table 6. Preparation procedure Composition Diltiazemi hydrochloridum
Amount
%
100.0
32.7
6.0
2.0
200.0
65.3
Povidonum Aqua purificata
Preparation procedure: Prepare the solution of diltiazem in the first step. Add the purified water in parts to the diltiazem hydrochloride with stirring. Dissolving takes place in the homogenizer with an adjustable rotation speed. After the dissolution of the drug add povidone (Kollidon 25) and after its dissolution, filter the dispersion. In the second step, apply the drug solution to 200 g of indifferent Celphere pellets (inactive cores) with a particle size of 1.0 mm. Particles should be placed in an apparatus and heated to a temperature of 45 °C at 80 °C air inflow. On the heated cores is applied a solution at spraying speed of 10 to 30 g/min (starting at 10 g/min and gradually increase). Inlet air temperature should be adjusted to 65 °C, product temperature to 45 °C. The last step is drying the product at a temperature of inlet air of 80 °C and 45 °C of product. The produced pellets are evaluated for overall yield, particle size distribution by sieving analysis, friability, shape and density (see Chapter 3. Quality evaluation methods).
SPRAY AGGLOMERATION Based on the principle of liquid surface tension, and thus on the effort of liquids to form units with the smallest surface, pelletization methods like: spray drying and spray cooling (congealing), are used. The spray drying process involves the injection of drugs, or drugs and excipients, in a solution or suspension form into a chamber with a stream of hot air, where the solvent evaporates while the dry porous pellets of spherical shape are formed. In spray cooling, the drug is melted, dissolved or dispersed in suitable melted excipients (wax, triglyceride) and then injected into the chamber with a temperature below the melting temperature of individual components. Recently, there are also used some inovative pelletization techniques such as: cryopelletization or melt extrusion.
49
2.
Rectal and vaginal drug forms
2.1 Rectal drugs Rectal preparations are intended for rectal use in order to obtain a systemic or local effect, or they may be intended for diagnostic purposes (Ph. Eur. 7). Several categories of rectal preparations may be distinguished: suppositories, rectal capsules, solutions, emulsions and suspensions, powders and tablets for rectal solutions and suspensions, semi-solid rectal preparations, rectal foams and tampons. Rectal application could be suitable for drugs: With insufficient absorption in upper part of gastrointestinal tract Inactivated by the pH or enzymatic activity of the stomach or intestine fluids Irritable for upper part of gastrointestinal tract With dose higher than 500 mg With extensive pre-systemic elimination (first-pass effect) after oral administration With really unpleasant taste and odor Rectal application is suitable for children, geriatric patients, patients with swallowing problems (i.e. postoperative states, burning of esophagus by acids or hydroxides), vomiting patients (i.e. migraine, motion sickness) and patients with mental disorders. Preparations with a local effect are used for the treatment of problems associated with hemorrhoids, for a laxative effect and for the therapy of IBD (Inflammatory bowel diseases) located in rectum.
2.1.1 Suppositories Suppositories are solid, single-dose preparations. The shape, volume and consistency of suppositories are suitable for rectal administration. They contain one or more active substances dispersed or dissolved in a suitable base that may be soluble or dispersible in water or may melt at body temperature. Suppositories can contain other excipients, such as diluents, colouring agents, adsorbents, surface-active agents, lubricants, preservatives, etc. 50
Suppositories are prepared by molding or cold compression. The mainly used suppository bases are cocoa butter (theobroma oil – especially used in pharmacy), hydrogenated vegetable oil bases (hard fat), polyethylen glycols and gel bases. The suppository base and drug(s) are weighed before preparation. However, the molding method is based on volumetric principle (the cavities of the mold are filled according to their volume). This can lead to some inaccuracies, which could be corrected by calculating the required amount of suppository base using three main coefficients or by experimental preparation of suppositories. Three main correction coefficients are used for the calculation of the required amount of suppository base: Calibration coefficient Loss coefficient Base replacement coefficient
Calibration coefficient It is the ratio of the real and theoretical weight of a supporitory. The aim is to find out the real weight of a suppository obtained from the used mold (it can be applied to a specific base in some degree of melting). Equation: C = A/B
C……calibration coefficient – for individual mold and suppository base in some degree of melting A……real average suppository weight – obtained experimentally B……theoretical suppository weight (according to the mold – 1 g – for children, 2 g – for adults, 3 g – for vaginal pessaries) Real suppository weight is calculated by multiplying the theoretical weight of the suppository and calibration coefficient. Example 1: the average weight of suppositories for adults prepared by molding is 1.9 grams, then calibration coefficient C = 1.9 / 2.0 = 0.95. 51
Example 2: average real weight of suppository prepared by molding in mold with calibration coefficient 0.95 is 2 x 0.95 = 1.9 g.
Loss coefficient It is defined as the loss of the suppository base with drug during preparation. It ranges from 2 to 10 %. Therefore, it is necessary to add some amount to correct this loss (adding not only base but also drug). For adults suppositories: add base (also drug) for 1 supp., when 10 – 20 suppositories are prepared. For children suppositories: add base (also drug) for 2 supp., when 10 – 20 suppositories are prepared.
Base replacement coefficient It is defined as the weight of the suppository base (g), which is displaced by 1 g of drug (base replacement coefficient 0.7 means that 1 g of drug displaces 0.7 g of suppository base). There are three possibilities of how to find out the value of the base replacement coefficient. Firstly, we can find its value in special tables (for individual drug and suppository base – see Table). Secondly, if the value of the base replacement coefficient is not in the tables, we can use the universal value 0.7 for organic compounds. The third possibility is to determine the value of the base replacement coefficient experimentally.
Experimental determination of base replacement coefficient Procedure: Prepare 10 suppositories from the blank suppository base (cocoa butter or hard fat) and weigh them together - weight A Prepare 10 suppositories from the suppository base with drug in a special way – weight B:
52
For mold for children suppositories: Take only 6-7 g of suppository base and melt it. Add 1 g of tested drug. Pour the melted material into ten cavities of the mold. Each cavity is only partially filled with melted material. Fill the rest of the space in each cavity by the blank suppository base. Scrape off the excessive base material after partial solidification. Weigh the prepared suppositories – weight B For mold of adult suppositories: Take 17 g of the suppository base and melt it. Add 2 g of the tested drug. Pour the melted material into ten cavities of the mold. Each cavity is only partially filled with melted material. Fill the rest of the space in each cavity with the blank suppository base. Scrape off the excessive base material after partial solidification. Weigh the prepared suppositories – weight B Base replacement coefficient is calculated according to the equation:
A – (B – a) f = a f………………
base replacement coefficient
a………………
weight of drug (g) incorporated in 10 suppositories
A……………..
weight of 10 suppositories from blank base (g)
B……………… weight of 10 suppositories from base containing drug (g) Then the determined base replacement coefficient of the drug can be used repeatedly for different molds if the parameters of preparation (suppository base, particle size of drug, degree of melting) are the same. Calculation of required amount of suppository base
53
a) if the value of base replacement coefficient is known:
x = M – (f1*m1 + f2*m2 + … + fn*mn) M = c.b.n x…………….. required amount of suppository base M……………
real weight of all prepared suppositories from blank base
c…………….. calibration coefficient of mold b…………….. theoretical weight of one prepared suppository (g) n…………….. number of prepared suppositories f1, f2, fn………
base replacement coefficient for drug (from drug 1 to n)
m1, m2, mn ….
weight of drug (from drug 1 to n) in all prepared suppositories
If content of drug is less than 5 % of suppository weight, it is not necessary to include this drug into calculation.
54
Table 7: Base replacement coefficients of selected drugs and excipients for cocoa butter and hard fat
Name of drug or excipient
Base replacement coefficient Cocoa butter
Acidum boricum
0.67
Acidum acetylsalicylicum
0.65
Acidum salicylicum
0.71
Aminophenazonum
0.78
Balsamum peruvianum
0.83
Barbitalum
0.81
Belladonnae extractum siccum
0.75
Bismuthi subgallas
0.37
Camphora
1.49
Cera alba
1.0
Hard fat 0.62 0.68 0.72
0.98
Codeini phosphas
0.80
Ethylmorphini hydrochloridum
0.71
Glycerolum 85 %
0.78
0,75
Ichthammolum
0.91
0.72
Mentholum
1.52
1.08 0.89
Papaverini hydrochloridum Paraffinum solidum
1.0
Phenacetinum
0.63
0.61 0.62
Phenobarbitalum Quinini hydrochloridum
0.83
Resorcinolum
0.71
0.43
Sulfathiazolum
0.62
0.48
Zinci oxidum
0.2
Experimentally, if the value of base replacement coefficient is not known:
55
EXAMPLE Rp. Coffeini
0.1
Acidi acetylsalicylici
0.25
Massae ad supp.
q.s.
Ut fiant supp. pro adult. D.t.d. No X (decem)
a)
b)
c)
Figure 6: Preparation of suppositories with unknown base replacement coefficient
Preparation procedure: Calculate with one suppository more (in the case of adult suppositories) as the loss coefficient. The procedure is very similar to the determination of the base replacement coefficient. Take the amount of drug(s) corresponding to the 11 suppositories but a significantly smaller amount of suppository base than expected, usually 1 g (or 1,5 g) of the suppository base for one suppository. Coffeinum
11 x 0.1 = 1.1 g
Acidum acetylsalicylicum
11 x 0.25 = 2.75 g
Massae ad suppositore
11 x 1.0 (1.5) = 11.0 (16.5) g 56
Take 11 g of the suppository base and melt it. Add 1.1 g of caffeine and 2.75 g of acetylsalicylic acid and mix it thoroughly. Pour the melted material into the 11 cavities of the mold. Each cavity is only partially filled with the melted material. Fill the rest of the space in each cavity by the blank suppository base. Scrape off the excessive base material after partial solidification. Obtain 11 suppositories (usually two-colored) with unevenly dispersed drugs. Consequently, the prepared two-colored suppositories are grated or cut into small pieces. These are carefully melted, homogenized and poured into 10 cavities (see Figure 6). Final suppositories are weighed and the amount of blank suppository base required for one suppository is calculated according to the equation:
B – (m1 + m2) x = n where: x……………… amount of blank suppository base required for one suppository (g) B…………….
weight of all suppositories containing drug(s) (g)
m1, m2……………
weight of drugs in 10 suppositories
n……………… number of suppositories
General rules for supporitories preparation Check carefully the maximal individual and daily dose of the drug for adults and therapeutical individual and daily dose of drug for children Drug suspended in the suppository base should be comminuted to the required particle size (optimum about 100 µm). The suppository base is melted over the water bath or under the infrared lamp. The molten suppository base with or without drug(s) must be homogenous. The blank suppository basis can be melted under an infrared lamp; the drug is added into the molten base. The suppository base with the incorporated drug should be preferably melted over the water bath to protect the 57
drug against against high change of temperature. During the melting, it is necessary to mix the material thoroughly. For uniform melting, it is suitable to take the mortar out of the heat source, from time to time. The molten material of suitable consistency is poured into: metallic molds - individual suppositories are obtained, each suppository must be packed in the aluminum or cellophane foils, the surface of the cavities of metallic molds should be lubricated to ensure the easy removal of suppositories. For lipophilic bases (cocoa butter, hard fat) we use hydrophilic liquid (ethanolic solution of potassium soap, glycerol), for hydrophilic bases the lipophilic liquids are used (liquid paraffin, plant oils). For bases with a high volume contractility (hard fat) or if the mold surface is coated with a non-stick material (teflone, silicone), the lubrication of the mold is not necessary. The disposable molds from plastic or flexible rubber materials – are used as the primary package. The suppository forming mixture is poured in a thin stream into the mold; the material is constantly stirred especially when the suppositories with the suspended drug are prepared. To ensure the complete filling of the cavities of the mold when solidified, a small excess of molten mixture is poured over each cavity. When partially solidified, the excessive material can be scraped off from the top of the mold with a spatula (see Figure 7). Consequent solidification can take place in the refrigerator for quicker hardening, never in freezer (rapid cooling of suppositories in the freezer leads to obtaining low-quality suppositories).
Figure 7
58
EXAMPLES Pharmacopoeial suppository : Glyceroli suppositorium – Glycerol suppository. Exercise 2.1.1.1 Glyceroli suppositorium – Glycerol suppository Natrii carbonas decahydricus
2.5
Acidum stearicum
4.5
Glycerolum 85 %
50.0
Aqua purificata
q.s.
Preparation procedure: Heat sodium carbonate and stearic acid with glycerol over a water bath up to the termination of neutralization and add evaporated water to 50.0 g. Pour the prepared material into the cavities of the mold. Exercise 2.1.1.2 Rp. Bismuthi subgallatis
1.0
Cacao olei
q.s.
Ut fiant supp. pro infantibus Div. in dos.aeq. No X (decem) D.S. Apply 1 suppository in the evening Exercise 2.1.1.3 Rp. Sulfathiazoli
5.0
Cacao olei
q.s.
Ut fiant supp. pro adult. Div. in dos. aeq. No X (decem) D.S. Apply 1 suppository 3 times a day
59
Exercise 2.1.1.4 Rp. Ketazoni
0.5
Cinchocaini hydrochloridi
0.015
Massae ad supp.
q.s.
Ut fiant supp. pro adult. D.t.d. No X (decem) D.S. Apply 1 suppository in the evening Exercise 2.1.1.5 Rp. Ergotamini tartratis
0.001
Coffeini
0.1
Phenobarbitali
0.02
Cacao olei
q.s.
Ut fiant supp. pro adult. D.t.d. No X (decem) D. S. Apply 1 suppository when pain (max. 1 supp. 3 times a day) Exercise 2.1.1.6 Rp. Codeini phosphatis
0.03
Phenobarbitali
0.15
Massae ad supp.
q.s.
Ut fiant supp. pro infant. Div. in dos. aeq. No X (decem) D. S. Apply 1 suppository in the evening
60
Exercise 2.1.1.7 Rp. Belladonnae extr. sicc.
0.003
Indomethacini
0.1
Codeini phosphatis
0.01
Coffeini
0.05
Massae ad supp.
q.s.
Ut fiant supp. pro adult. D.t.d. No X (decem) D. S. Apply 1 suppository in the evening Exercise 2.1.1.8 Rp. Paracetamoli
0.2
Cacao olei
q.s.
Ut fiant supp. pro infantibus D.t.d. No X (decem) D. S. Apply 1 suppository when fever (max. 1 supp. 3 times a day) Exercise 2.1.1.9 Rp. Ketazoni
5.0
Massae ad supp.
q.s.
Ut fiant supp pro adult. Div. in dos. aeq. No X (decem) D. S. Apply 1 suppository in the evening
61
Exercise 2.1.1.10 Rp. Papaverini hydrochloridi
0.04
Phenobarbitali
0.015
Massae ad supp.
q.s.
Ut fiant supp. pro infant. D.t.d. No X (decem) D. S. Apply 1 suppository in the evening
2.2 Vaginal drugs Vaginal preparations are liquid, semi-solid or solid preparations intended for administration to the vagina usually in order to obtain a local effect. They contain one or more active substances in a suitable base (Ph. Eur. 7). Several categories of vaginal preparations may be distinguished: pessaries, vaginal tablets, vaginal capsules, vaginal solutions, emulsions and suspensions, tablets for vaginal solutions and suspensions, semi-solid vaginal preparations, vaginal foams and vaginal tampons.
2.2.1 Vaginal pessaries (vaginal globules, vaginal suppositories) Pessaries are solid, single-dose preparations. They have various shapes, usually ovoid, with a volume and consistency suitable for the insertion into the vagina. They contain one or more active substances dispersed or dissolved in a suitable base that may be soluble or dispersible in water or may melt at body temperature. Pessarries are usually prepared by molding. The lipophilic (cocoa butter, hard fat) and hydrophilic bases (glycero-gelatin gel, polyethylene glycols) can be used. Lipophilic bases are preferably used, if there is a strong vaginal secretion or if the type of base is not specified. Vaginal pessaries can contain other excipients, such as solvents, coloring agents, adsorbents, surface-active agents, preservatives, etc. Lipophilic vaginal pessaries usually contain suspended drugs. The steps of their preparation are the same as lipophilic suppositories with suspended drugs. 62
Common base for hydropilic vaginal pessaries is glycero-gelatin gel (CP 2009): Gelatina
12.5
Aqua conservans
25.0
Glycerolum 85%
62.5
Preparation of glycero-gelatin gel Lay powdered gelatin on the surface of water (with preservatives) and let swell for 15 minutes Add glycerol 85% Heat the beaker over the water bath with the temperature not more than 70 °C until gelatin is dissolved Replace water that evaporated to the total amount of 100 grams and mix gently. Pour the prepared dispersion in the cavities of mold
Preparation of vaginal pessaries from glycero-gelatin gel – Starke's method First, the blank vaginal pessaries (without drug) are prepared. Dissolve the required number of blank vaginal pessaries (1 more to replace the loss) and mark the liquid surface with a line Remove part of dispersion to another beaker and add drug(s) After drug dissolving or suspending refill previously removed glycero-gelatin gel up to the line. Mix the dispersion and pour into the cavities of the mold In preparing the pessaries from different bases, we must take into account the design of forms. The cavities are filled through a narrow opening – neck, that is extended to the spherical cavities. The longer neck of the pessary is usually removed. In this case, it is necessary to ensure the accurate amount of the drug in the pessary without neck. For this purpose, we calculate the recalculating coefficient, which is defined as the ratio of the weight of pessary from blank base with and without neck. This coefficient is determined
63
experimentally for individual molds. Then, the prescribed amount of drug is multiplied by this coefficient. Pharmacopoeal pessaries: Natrii tetraboratis globulus – Pessary with sodium tetraborate Sulfathiazoli globulus – Pessary with sulfathiazole
EXAMPLES Exercise 2.2.1.1 Natrii tetraboratis globulus – Pessary with sodium tetraborate Natrii tetraboras decahydricus
0.3
0.6
Glycerogelatum gelatinae
q.s.
q.s.
Preparation procedure: Dissolve decahydrate of sodium tetraborate in melted glycerol-gelatin gel, mix it and pour it into the cavities of suitable mold. Exercise 2.2.1.2 Rp. Sulfathiazoli
0.5
Massae ad suppos.
q.s.
Ut fiant globul. vagin. D.t.d. No VI (sex) D.S. 1 pessary in the evening Exercise 2.2.1.3 Rp. Chloramphenicoli
0.2
Massae ad suppos.
q.s.
Ut fiant globul. vagin. D.t.d. No VI (sex) D.S. Apply 1 pessary 2 times a day 64
Exercise 2.2.1.4 Rp. Ichthammoli
3.5
Glycerogelati gelatinae
q.s.
Ut fiant glob. vagin. Div. in dos. eq. No VI (sex) D.S. Apply 1 pessary 2 times a day Exercise 2.2.1.5 Rp. Sulfathiazoli
0.5
Glycerogelati gelatinae
q.s.
ut fiant glob. vagin. D.t.d. No X (decem) D.S. 1 pessary in the evening Exercise 2.2.1.6 Rp. Tetracaini hydrochloridi
0.003
Natrii tetraboratis
0.3
Glycerogelati gelatinae
q.s.
ut fiant glob. vagin. D.t.d. No X (decem) D.S. 1 pessary in the evening
65
3.
Evaluations
3.1 Uniformity of content of single-dose preparations The test for uniformity of content of single-dose preparations is based on the assay of the individual contents of active substance(s) of a number of single-dose units to determine whether the individual contents are within limits set with reference to the average content of the sample. The test is not required for multivitamin and trace-element preparations and in other justified and authorised circumstances. Method: Using a suitable analytical method, determine the individual contents of active substance(s) of 10 dosage units taken at random. Apply the criteria of test A, test B or test C as specified in the monograph for the dosage form in question.
TEST A Tablets, powders for parenteral use, ophthalmic inserts, suspensions for injection. The preparation complies with the test if each individual content is between 85 % and 115 % of the average content. The preparation fails to comply with the test if more than one individual content is outside these limits or if one individual content is outside the limits of 75 % to 125 % of the average content. If one individual content is outside the limits of 85 % to 115 % but within the limits of 75 % to 125 %, determine the individual contents of another 20 dosage units taken at random. The preparation complies with the test if not more than one of the individual contents of the 30 units is outside 85 % to 115 % of the average content and none is outside the limits of 75 % to 125 % of the average content.
TEST B Capsules, powders other than for parenteral use, granules, suppositories, pessaries. The preparation complies with the test if not more than one individual content is outside the limits of 85 % to 115 % of the average content and none is outside the limits of 75 % to 125 % of the average content. The preparation fails to comply with the test if more than 3 individual contents are outside the limits of 85 % to 115 % of the average content or if one or more individual contents are outside the limits of 75 % to 125 % of the average content. If 2 or 3 66
individual contents are outside the limits of 85 % to 115 % but within the limits of 75 % to 125 %, determine the individual contents of another 20 dosage units taken at random. The preparation complies with the test if not more than 3 individual contents of the 30 units are outside the limits of 85 % to 115 % of the average content and none is outside the limits of 75 % to 125 % of the average content.
3.2 Uniformity of mass of single-dose preparations Weigh individually 20 units taken at random or, for single-dose preparations presented in individual containers, the contents of 20 units, and calculate the average mass, the individual masses deviates from the average mass and determine if these deviates are in Pharmacopoea limits. Not more than 2 of the individual masses deviate from the average mass by more than the percentage deviation shown in Table and none deviates by more than twice that percentage.
Table 8. Percentage deviation of mass for solid dosage forms Pharmaceutical Form
Average Mass
Tablets (uncoated and film- 80 mg or less coated) More than 80 mg and less than 250 mg 250 mg or more
Percentage deviation 10 7.5 5
* When the average mass is equal to or below 40 mg, the preparation is not submitted to the test for uniformity of mass but to the test for uniformity of content of single-dose preparations
3.3 Uniformity of dosage units To ensure the consistency of dosage units, each unit in a batch should have a drug substance content within a narrow range around the label claim. Dosage units are defined as dosage forms containing a single dose or a part of a dose of drug substance in each unit. The uniformity of dosage units specification is not intended to apply to suspensions, emulsions, or gels in unit-dose containers intended for topical administration. 67
The term “uniformity of dosage unit” is defined as the degree of uniformity in the amount of the drug substance among dosage units. Therefore, the requirements of this chapter apply to each drug substance being comprised in dosage units containing one or more drug substances, unless otherwise specified in the individual monograph. The uniformity of dosage units can be demonstrated by either of two methods, content uniformity or weight variation (see Table 8). The test for content uniformity is based on the assay of the individual content of drug substance(s) in a number of individual dosage units to determine whether the individual content is within the limits set. The content uniformity method may be applied in all cases. The test for content uniformity is required for those dosage forms described in table 8. Table 8. The content uniformity method for individual dosage forms Dosage form
Type
Tablets
Uncoated Coated
Capsules
Hard Soft
Subtype
Film Others Suspension, Emulsion. or gel Solutions
Dose and Ration of Drug substances > 25 mg and <25 mg and or > 25 % <25 % WV CU WV CU CU CU WV CU CU CU
Solutions in unit dose containers and into soft capsules CU…content uniformity; WV…weight variation
WV WV
WV WV
Content uniformity Uncoated and coated tablets, or capsules, oral solutions in unit-dose containers, suspensions or emulsions or gels in single-unit containers (that are intended for systemic administration only), and solids (including sterile solids) in single-unit containers — assay 10 units individually and calculate the acceptance value as directed below.
68
Table 9. Calculation of acceptance criterium Variable Definition Mean of individual contents X ( 1, 2, … , n), expressed as a percentage of the label claim Individual contents of the 1, 2, … , n units tested, expressed as a percentage of the label claim n Sample size (number of units in a sample) k Acceptability constant
s
Standard sample deviation
RSD
Relative standard deviation (the sample standard deviation expressed as a percentage of the mean) Reference value
M (case 1) to be applied when T 101.5
M (case 2) to be applied when T>101.5
Conditions
Value
If then n = 10 If then n = 30 If then n = 30 If then n = 30
2.4 2.0 2.0 2.0
f 98.5% X 101.5%, then If X <98.5%, then
M=X (AV = ks)
M = 98.5% (AV = 98.5 – X + ks) If X >101.5%, then M = 101.5% (AV = X – 101.5 +ks) M=X (AV = ks) If 98.5 X T, then
Reference value
If X <98.5%, then If X >T, then Acceptance value (AV) L1 L2
Maximum allowed acceptance value Maximum allowed range for On the low side, no 69
M = 98.5% (AV = 98.5 – X + ks) M = T% (AV = X – T + ks)
L1 = 15.0 unless otherwise specified L2 = 25.0 unless
Variable
Definition deviation of each dosage unit tested from the calculated value of M
Conditions Value dosage unit result can otherwise specified in be less than [1 – the individual (0.01)(L2)]M,while on monograph the high side no dosage unit result can be greater than [1 + (0.01)(L2)]M. (This is based on an L2 value of 25.0.)
T
Target content per dosage unit at the time of manufacture, expressed as a percentage of the label claim. For purposes of this Pharmacopeia, unless otherwise specified in the individual monograph, T is the average of the limits specified in the potency definition in the individual monograph. Sample standard deviation is calculated according to equation:
Weight variation Select not fewer than 30 dosage units, and proceed as follows for the dosage form designated. The result of the Assay, obtained as directed in the individual monograph, is designated as result A, expressed as % of label claim (see Calculation of Acceptance Value). Assume that the concentration (weight of drug substance per weight of dosage unit) is uniform. [Note Specimens other than these test units may be drawn from the same batch for assay determinations.] Uncoated or Film-Coated Tablets — Accurately weigh 10 tablets individually. Calculate the drug substance content, expressed as % of label claim, of each tablet from the weight of the individual tablet and the result of the Assay. Calculate the acceptance value. Hard Capsules — Accurately weigh 10 capsules individually, taking care to preserve the identity of each capsule. Remove the contents of each capsule by a suitable means. Accurately weigh the emptied shells individually, and calculate for each capsule the net weight of its contents by subtracting the weight of the shell from the respective gross weight. Calculate the
70
drug substance content, expressed as % of label claim, of each capsule from the net weight of the individual capsule content and the result of the Assay. Calculate the acceptance value. Soft Capsules — Accurately weigh 10 intact capsules individually to obtain their gross weights, taking care to preserve the identity of each capsule. Then cut open the capsules by means of a suitable clean, dry cutting instrument such as scissors or a sharp open blade, and remove the contents by washing with a suitable solvent. Allow the occluded solvent to evaporate from the shells at room temperature over a period of about 30 minutes, taking precautions to avoid uptake or loss of moisture. Weigh the individual shells, and calculate the net contents. Calculate the drug substance content, expressed as % of label claim, in each capsule from the net weight of product removed from the individual capsules and the result of the Assay. Calculate the acceptance value. Calculation of Acceptance Value — Calculate the acceptance value as shown in Content Uniformity, except that the individual contents of the units are replaced with the individual estimated contents defined below. . 1,
2,
... ,
n
=
w1, w2, ... , wn A
= =
W
=
individual estimated contents of the units tested, where i = wi × A / W individual weights of the units tested, for weight variation, content of drug substance (% of label claim) determined as described in the Assay, and mean of individual weights (w1, w2, ... , wn) of the units used in the Assay.
Criteria Apply the following criteria, unless otherwise specified in the individual monograph. Uncoated, Coated, or Molded Tablets, Capsules, Oral Solutions in Unit-Dose Containers, Suspensions or Emulsions or Gels in Single-Unit Containers (that are intended for systemic administration only), and Solids (including Sterile Solids) in Single-Unit Containers— The requirements for dosage uniformity are met if the acceptance value of the first 10 dosage units is less than or equal to L1%. If the acceptance value is greater than L1%, test the next 20 units, and calculate the acceptance value. The requirements are met if the final acceptance value of the 30 dosage units is less than or equal to L1%, and no individual content of any dosage unit is less than [1
(0.01)(L2)] M nor more than [1 + (0.01)(L2)] M as specified in 71
the Calculation
of
Acceptance
Value under Content
Uniformity or
under
weight
Variation. Unless otherwise specified in the individual monograph, L1 is 15.0 and L2 is 25.0.
3.4 Particle size distribution The standard particle size analysis test determines the relative proportions of different grain sizes as they are distributed among certain size ranges. Particle size distribution is an important characteristic of solid dosage forms. The particle size of the drug substance and excipients affects the quality of the preparation and formulation. The particle size of granules and powders affects mutual mixing and uniformity of the mixture reached. It also affects their flowability. Particle size also affects the rate of dissolution for poorly soluble drugs. In addition to the methods below, there are many other method such microscopically analysis, laser diffraction etc.
3.4.1 Sieve analysis For coarser powders, granules, pellets or microparticles with sizes above the 40 micron sieve analysis is used. A representative weighed sample (minimaly 25 g) is given on the top sieve which has the largest screen openings. Each lower sieve in the column has smaller openings than the one above. The column is typically placed in a mechanical shaker. The shaker shakes the column of sieves, usually for some fixed amount of time. After the shaking is complete the material on each sieve is weighed. The weight of the sample of each sieve is then divided by the total weight to give a percentage retained on each sieve.
Figure 8. Sieve analysis 72
It is determined by two variables: particle size distribution and average particle diameter, which is calculated by the following formula: n
d
xi.di i1
100
d…average diameter xi…average size of the upper and lower mesh of sieve of fraction i di…percentage by weight of fraction n…number of sieves
3.5 Bulk and tapped density Bulk density is determined by placing a sample of 100 g of powder (granules) of known weight in a graduated cylinder (250 ml). Tapped density is determined by tapping the powder in the graduated cylinder until it no longer settles. The compressibility index and the Hausner ratio are determined by measuring both the bulk volume and tapped volume of a powder.
3.5.1 Compressibility index or Hausner ratio In recent years the compressibility index (CI) and the closely related Hausner ratio have become the simple, fast, and popular methods of predicting powder flow characteristics. Both parameters has been proposed as an indirect measure of bulk density, size and shape, surface area, moisture content, and cohesiveness of materials, because all of these can influence the observed compressibility index. Bulk or tapped density is a measure of the degree of packing or, conversely, the amount of space between the particles in the powder. Measure the bulk volume V0 and the final tapped volume Vf (i.e., in V1250 or in V2500), as described in Section 3.5. 250 ml graduated cylinder and 100 g of sample are used for testing. It may also been used a smaller amount of sample and the volume of the cylinder. Perform three measurements and determine the mean value. The compressibility index and Hausner ratio is calculated by the formula: V0 Vf (3) CI = 100 V0
tapped bulk
or CI = 100
tapped
73
tapped V0 (4) HR = V or HR = f bulk Table 10. Scale of powder (granules) flowability. Compressibility index (%)
Flow character
Hausner ratio
1-10
Excellent
1.00-1.11
1-15
Good
1.12-1.18
16-20
Fair
1.19-1.25
21-25
Passable
1.26-1.34
26-31
Poor
1.35-1.45
32-37
Very poor
1.46-1.59
> 38
Very, very poor
> 1.60
3.6 Flowability During many pharmaceutical production processes, it is necessary to transfer large quantities of powder from one location to another in a controlled manner. E.g., powder blending, powder filling into the dies of a tablet press, powder flow into capsules and etc. For this reason, the powders for pharmaceutical use must have a sufficient properties of flowing. The fluidity of powder is influenced by various properties of the particles, such as particle size and its distribution, shape and surface roughness of the particles, moisture, and interparticle forces. The fluidity of a powder can be improved by changing its physical properties, such as moisture content and particle size and shape, by drying, grinding, classification and granulation. Flowability is the ability of powder (granules) to flow in a desired manner is a specific piece of equipment. Flowability test The test for flowability is intended to determine the ability of divided solids (e.g. powders and granules) to flow vertically under defined conditions.
74
Apparatus According to the flow properties of the material to be tested, funnels with or without stem, with different angles and orifice diameters are used. Typical apparatuses are shown in Figure 9. The funnel is maintained upright by a suitable device. The assembly must be protected from vibrations. Method Into a dry funnel, whose bottom opening has been blocked by suitable means, introduce without compacting a test sample weighed with 0.5 % accuracy. The amount of the sample depends on the apparent volume and the apparatus used. Unblock the bottom opening of the funnel and measure the time needed for the entire sample to flow out of the funnel. Carry out three determinations. Results The flowability is expressed in time unit, related to 100 g of sample. The results depend on the storage conditions of the material to be tested. The results can be expressed as the following: a) the mean of the determinations, if none of the individual values deviates from the mean value by more than 10 %; b) as a range, if the individual values deviate from the mean value by more than 10 %; c) as a plot of the mass against the flow time; d) as an infinite time, if the entire sample fails to flow through. Typical aparatus for the test of powder (granules) flowability.
75
Figure 9.Funnel Table. 11 The sizes of nozzles, which can be used for the flowability test. Nozzle
Diameter of the outflow opening (mm) 1
10 ± 0.01
2
15 ± 0.01
3
25 ± 0.01
Powder flow The widespread use of powders in the pharmaceutical industry has generated a variety of methods for characterising powder flow. Four commonly reported methods for testing powder flow are: Angle of repose, Compressibility index or Hausner ratio, Flow rate through an orifice, Shear cell. The development of such a variety of test methods was inevitable; powder behavior is multifaceted and thus complicates the effort to characterise powder flow.
76
3.7 Friability of uncoated dosage forms This test serves for the friability determination of compressed, uncoated tablets. It brings information about tablets (pellets) mechanical properties which are important for other processing, such as coating or packaging. Friability means damage of tablets (pellets) by mechanical stress under defined conditions. Within this test, the tablets (pellets) roll or slide and fall onto the drum wall or onto each other. Measurement of tablet (pellets) friability supplements other physical strength measurements, such as tablet (pellets) breaking force. Method Use a plastic drum, with an internal diameter between 283-291 mm and a depth between 3640 mm, of transparent synthetic polymer with polished internal surfaces, and subject to minimum static build-up (see Figure 9). For tablets with a unit mass equal to or less than 650 mg, take a sample of whole tablets corresponding as near as possible to 6.5 g. The tablets are carefully dedusted prior to testing. Accurately weigh the tablet sample, and place the tablets in the drum. Rotate the drum 100 times (4 minutes, 25 rpm), and remove the tablets. Remove any loose dust from the tablets as before, and accurately weigh. For pellets take sample of 10 g. The test sample is placed in the metal drum together with 200 glass beads (4 mm in diameter). Rotate the drum 200 times (10 minutes, 20 rpm). Results For tablets, a maximum loss of mass (obtained from a single test or from the mean of 3 tests) not greater than 1.0 % is considered acceptable for most products. Generally, the test is run once. If obviously cracked, cleaved, or broken tablets are present in the tablet sample after tumbling, the sample fails the test. If the results are difficult to interpret or if the weight loss is greater than the targeted value, the test is repeated twice and the mean of the 3 tests determined.
77
Figure 10. Friabilator
3.8 Resistance to crushing of tablets (hardness) This test is intended to determine, under defined conditions, the resistance to crushing of tablets, measured by the force needed to disrupt them by crushing. Apparatus The apparatus consists of 2 jaws facing each other, one of which moves towards the other. The flat surfaces of the jaws are perpendicular to the direction of movement. The crushing surfaces of the jaws are flat and larger than the zone of contact with the tablet. The apparatus is calibrated using a system with a precision of 1 N. Method Place the tablet between the jaws, taking into account, where applicable, the shape, the breakmark and the inscription; for each measurement orient the tablet in the same way with respect to the direction of application of the force. Carry out the measurement on 10 tablets, taking care that all fragments of tablets have been removed before each determination. Expression of results Express the results as the mean, minimum and maximum values of the forces measured, all expressed in N. Indicate the type of apparatus and, where applicable, the orientation of the tablets.
78
The following formula can be used for determibation of tensile strenght independent on tablet: 2F
f(s) dv
size:
0,4F Similar formula for pellets: f(s) r2
where
f(s) ………... tensile strength F ………….. crushing force d ………….. tablet diameter v ………….. tablet thickness r …………
pellets radius
The unit of tensile strength is N.m2 or Pa.
3.9 Disintegration of tablets and capsules This test is provided to determine whether tablets or capsules disintegrate within the prescribed time when placed in a liquid medium under the experimental conditions presented below. Apparatus (for tablets and capsules not greater than 18 mm) The apparatus consists of a basket-rack assembly, a 1 litre, low-form beaker for the immersion fluid, a thermostatic arrangement for heating the fluid between 35 °C and 39 °C, and a device for vertical movement of the basket in the immersion fluid at a constant frequency rate between 29 and 32 cycles per minute. The basket-rack assembly consists of 6 open-ended transparent tubes, each 77.5 ± 2.5 mm long and having an inside diameter of 21.85 ± 1.15 mm and a wall 1.9 ± 0.9 mm thick; the tubes are held in a vertical position by 2 plates, each 90 ± 2 mm in diameter and 6.75 ± 1.75 mm in thickness, with 6 holes, each 24 ± 2 mm in diameter, equidistant from the centre of the plate and equally spaced from one another. Attached to the under surface of the lower plate is a woven stainless steel wire cloth, which has a plain square weave with 2.0 ± 0.2 mm mesh apertures and with a wire diameter of 0.615 ± 0.045 mm. The parts of the apparatus are assembled and rigidly held by means of
79
3 bolts passing through the 2 plates. A suitable means is provided to suspend the basket-rack assembly from the raising and lowering device using a point on its axis. The design of the basket-rack assembly may be varied somewhat provided the specifications for the glass tubes and the screen mesh size are maintained. The basket-rack assembly conforms to the dimensions shown in Figure 10. Discs. The use of discs is permitted only where specified or allowed. Each tube is provided with a cylindrical disc 9.5 ± 0.15 mm thick and 20.7 ± 0.15 mm in diameter. The disc is made of a suitable, transparent plastic material having a specific gravity of 1.18-1.20. 5 parallel 2 ± 0.1 mm holes extend between the ends of the cylinder. One of the holes is centered on the cylindrical axis. The other holes are centered 6 ± 0.2 mm from the axis on imaginary lines perpendicular to the axis and parallel to each other. 4 identical trapezoidal-shaped planes are cut into the wall of the cylinder, nearly perpendicular to the ends of the cylinder. The trapezoidal shape is symmetrical; its parallel sides coincide with the ends of the cylinder and are parallel to an imaginary line connecting the centres of 2 adjacent holes 6 mm from the cylindrical axis. The parallel side of the trapezoid on the bottom of the cylinder has a length of 1.6 ± 0.1 mm and its bottom edges lie at a depth of 1.5 mm to 1.8 mm from the cylinder’s circumference. The parallel side of the trapezoid on the top of the cylinder has a length of 9.4 ± 0.2 mm and its centre lies at a depth of 2.6 ± 0.1 mm from the cylinder’s circumference. All surfaces of the disc are smooth. If the use of discs is specified, add a disc to each tube and operate the apparatus as directed under Procedure. The discs conform to the dimensions. The use of automatic detection employing modified discs is permitted where the use of discs is specified or allowed. Such discs must comply with the requirements of density and dimension given in this chapter. Procedure Place 1 dosage unit in each of the 6 tubes of the basket and, if prescribed, add a disc. Operate the apparatus using the specified medium, maintained at 37 ± 2 °C, as the immersion fluid. At the end of the specified time, lift the basket from the fluid and observe the dosage units: all of the dosage units have disintegrated completely. If 1 or 2 dosage units fail to disintegrate, repeat the test on 12 additional dosage units. The requirements of the test are met if not less than 16 of the 18 dosage units tested have disintegrated. 80
Figure 11. Basket-rack assembly for disisntehration
3.10 Dissolution test for oral solid dosage forms This test determines the amount of active ingredient(s) released from a solid oral dosage form, such as a tablet or a capsule, using a known volume of dissolution medium within a predetermined length of time. This test method may not be applicable to certain oral dosage forms. Apparatus All parts of the apparatus, including any metal that may come into contact with the sample to be tested or the dissolution medium, should be made from a chemically inert material and should not adsorb, react or interfere with the preparation or the dissolution medium. The dissolution assembly should be constructed in such a way that any vibration is reduced to a minimum. Use an apparatus that allows full visibility of all operations. The apparatus "Paddle" (Fig. 12) consists of a cylindrical vessel of suitable glass or other suitable transparent material with a hemispherical bottom and a nominal capacity of 1000 ml. The vessel is covered to prevent evaporation of the medium with a cover that has a central hole to accommodate the shaft of the stirrer and other holes for the thermometer and for devices for withdrawal of liquid. The stirrer consists of a vertical shaft with a blade at the 81
lower end. The blade is constructed around the shaft so that it is flush with the bottom of the shaft. When placed inside the vessel, the shaft's axis is within 2mm of the axis of the vessel and the bottom of the blade is 25 ± 2 mm from the inner bottom of the vessel. The upper part of the shaft is connected to a motor provided with a speed regulator so that smooth rotation of the stirrer can be maintained without any significant wobble. The apparatus is placed in a water-bath that maintains the dissolution medium in the vessel at 37 ± 0.5 °C. The apparatus "Basket" (Fig. 13) consists of the same apparatus as described for "Paddle", except that the paddle stirrer is replaced by a basket stirrer. The basket consists of two parts. The top part, with a vent, is attached to the shaft. It is fitted with three spring clips, or other suitable attachments, that allow removal of the lower part so that the preparation being examined can be placed in the basket. These three spring clips firmly hold the lower part of the basket concentric with the axis of the vessel during rotation. The lower detachable part of the basket is made of welded-seam cloth, with a wire thickness of 0.254 mm diameter and with 0.381 mm square openings, formed into a cylinder with a narrow rim of sheet metal around the top and the bottom. If the basket is to be used with acidic media, it may be plated with a 2.5-μm layer of gold. When placed inside the vessel, the distance between the inner bottom of the vessel and the basket is 25 ± 2mm.
82
Figure 12. Paddle Measurements in mm British Pharmacopoeia, 1999, Crown copyright material. Reproduced with the permission of the Controller of Her Majesty's Stationery Office. Test conditions The following specifications are given in the individual monographs: - the apparatus to be used; - the composition and volume of the dissolution medium; - the rotation speed of the paddle or basket; - the preparation of the sample and reference solutions; 83
- the time, the method, and the amount for sampling of the test solution or the conditions for continuous monitoring; - the method of analysis; and - the limits of the quantity or quantities of active ingredient(s) required to dissolve within a prescribed time.
Figure 13. Basket Measurements in mm.
84
Exercise Dissolution of tablets with content of 500 mg Magnesium lactate Test conditions: Apparatus: paddle Velocity: 100 pm Volume: 900 ml Medium: water Temperature 37oC End point: 30 min Procedure: 100 ml of dissolution medium (after 30 min of dissolution) is transferred into a 250 ml titration flask and diluted up to 200 ml by purified water. Add 10 ml with ammonium chloride solution (pH 10) and 50 mg eriochrome black with sodium chloride. Heat to 40° C and titrate with standard EDTA solution 0.02 mol/l to violet color. 1 ml of EDTA corresponds to 0.4862 mg.
3.11 Evaluation of content Test is performed with tablets containing acetylsalicylic acid (ASA). Method 1 tablet with ASA is powdered. Quantity of powder with content of 0.3500 g ASA is weighed (Do not weigh 0.3500 g !!!) and placed to the titration beaker. 50 ml of 95 % ethanol is weighed and add 5 drops of phenolphthalein and titrate by 0.1 M solution of NaOH to slightly red color. Add this solution (point 3) to the powder which contents 0.3500 g ASA (point 2). Mixture is titrated by 0.1 M solution of NaOH to the same slightly red color. 1 ml corresponds to 0.01802 g ASA.
85
Autors:
Kateřina Kubová Aleš Franc Jan Gajdziok Martina Kejdušová David Vetchý
Title:
MEDICAL FORMS AND BIOPHARMACY II.Solid Dosage Forms
Department:
Department of Pharmaceutics
Pages:
87
Edition:
1st
Publisher:
University of Veterinary and Pharmaceutical Sciences Brno
ISBN 978-80-7305-757-2
86