FORMULATION DEVELOPMENT AND MANUFACTURE OF POWDER DOSAGE FORMS

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FORMULATION DEVELOPMENT AND MANUFACTURE OF POWDER DOSAGE FORMS N.PRAVEEN KUMAR M.PHARMACY

Powders as Dosage Forms:

Powders as Dosage Forms Powders are both the simplest dosage forms and the basis of many other solid dosage forms, such as tablets, capsules, etc. Many drugs or ingredients are also in powder form before processing. Powders were originally designed as a convenient mode of administering hard vegetable drugs such as roots, barks, and woods; powders were also found to be convenient for dispensing insoluble chemicals such as calomel, bismuth salts, mercury, and chalk. Presentation in powder form permits drugs to be reduced to a very fine state of division, which often enhances their therapeutic activity or their efficacy by an increase of dissolution rate and/or absorption. Divided powders are also found to be convenient for administering drugs that are excessively bitter, nauseous, or otherwise offensive to the taste.

Formulation of powders:

Formulation of powders Obtention of powder as raw material from an original drug (animal, vegetable drugs, or animal or synthetic chemical entities) by different methods of division: Mixing of various powders with or without excipients as a function of the powders’ characteristics (e.g., flow properties) Modification of their density (e.g., by granulation) if Necessary Packaging of the finished product for an easy patient’s use

OBTENTION OF POWDERS AS RAW MATERIAL:

OBTENTION OF POWDERS AS RAW MATERIAL The main process is the mechanical division that reduces lump drugs into fragment of different sizes (coarse division). To reduce the size, communition is then used. Coarse division includes various operations such as cutting, chopping, crushing, grinding, milling, micronizing, and trituration, which depend on the type of equipment used, on the raw material to be treated (vegetable, synthetic, or mineral), and on the convenient particle size.

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Physical properties of the drug 1.Hardness : Hard substances must be subjected to compression , impact, and abrasion or milling , but equipment wear is severe. 2.Abrasiveness : This is measured on Moh’s scale: 1 3 ¼ soft substances, 8 10 ¼ hard substances . 3.Elasticity 4.Friability 5.Fribrousness: Plant products require a cutting or a chopping action and cannot be subjected to pressure or impact techniques. 6.Moisture content: recommend drying (moisture content <5%) the drug substances before communition (oven at 40–45C) to avoid liquefaction or agglomeration. Hydrates that may release their water during the process require cooling or low-speed processing.

Particle size:

Particle size A powder is characterized by its particle size, which is of importance in achieving optimum production of medicines. Influences the dissolution rate of the drug in vivo, Influences absorption rate and the onset of therapeutic activity. Particle size is important during the production of solid dosage forms in the manufacture of tablets and capsules.

Flow properties:

Flow properties Flow properties of powders are important parameters in mixing and segregation phenomena, essentially during storage. Depending on manufacturing and packaging processes, different flow characteristics are required that are essential for quality control and for the optimization formulation. So, it is necessary in most of the cases to add excipients for diluting the active powder drug, to improve the packaging properties, and/or to insure a good compliance from the patient (e.g., taste masking)

CLASSIFICATION AND EXAMPLES OF POWDERS AS DOSAGE FORMS:

CLASSIFICATION AND EXAMPLES OF POWDERS AS DOSAGE FORMS They can be classified as a function of their route of administration. Oral Administration Both single and multiple doses are available. Multiple-dose powders, presented in band or metal box, require a measure to deliver the prescribed dose. Currently, the best way is to use single dose contained in a folded paper (in community pharmacy) or sachets filled with the same accuracy as a tablet or capsule by a fully automatic machine. The sachet is made of paper, aluminum, and/or complex mixtures that are a combination of aluminum and plastic substances

Effervescent Powders.:

Effervescent Powders. Nowadays, effervescent powders are available in single or multiple units that contain acid substances and carbonates or bicarbonates, which quickly react in water by releasing carbon dioxide. They are dissolved or dispersed in water before being taken. This is a great advantage because the drug is then in solution, the pH of which is close to 7, which allows rapid passage through the pylorus. The drug absorption from the gut wall as well as the onset of therapeutic activity may thereby be hastened.

Effervescent powders contain:

Effervescent powders contain Acid materials : citric (monohydrate or anhydrate), tartaric,ascorbic (drug or excipient), fumaric, nicotinic, acetylsalicylic (as drug or excipient),malic, and adipic acids. Salts: sodium bicarbonate (the most widely used), sodium carbonate, potassium carbonate, calcium carbonate, sodium glycine carbonate. Other excipients (main characteristic, solubility in water) Lubricants: PEG 6000 is most frequently used, alone or with sodium stearyl fumarate, sodium benzoate, sodium chloride, sodium acetate, or D,L-leucine. Binders: PVP, hydrogenated maltodextrin, maltodextrins, PEG 6000. Others: sweeteners, flavors, colors, surfactants, antifoaming agents (polydimethylsiloxane)

Powders for Parenteral Use:

Powders for Parenteral Use For parenteral use, solid sterile substances are distributed in their final packages. A clear solution nearly free of particles or a uniform one is obtained after shaking with the prescribed volume of an appropriate sterile liquid. Freeze-dried substances for parenteral use are also used. After dissolution or dispersion, preparations must comply with assay requirements for injectable preparations or injectable preparations for perfusion. Their preparation requires the same care as parenteral solutions, i.e. sterilization of raw material or finished product sterilization.

Powders for Cutaneous Applications:

Powders for Cutaneous Applications These are single- or multiple-unit powders free of agglomerated particles. They must be sterile for application on open wounds or damaged skin Multiple-unit powders for local application are preferably packaged in a dredger or a pressurized container (for skin, teeth, or vaginal douche use). These preparations consist of a dispersion of a solid phase (drug) in a liquid propellant (liquid phase). By action on the actuator, the suspension is released by gas pressure. The propellant in contact with ambient air is evaporated and the powder remains on the treated area.

Powders for Pulmonary Application:

Powders for Pulmonary Application As a consequence of the suppression or reduced use of propellants, a new kind of dosage form is under worldwide development: drug powder inhalers (DPIs). The metered dose inhalers (MDIs) will probably be replaced by these. The MDIs were formulated several years ago. A drug in powder form (with a particle size close to 5 m m) was suspended in propellant 11 with a surfactant. Propellant 12 was added to the can after closure. The metered valve delivers a fixed volume of suspension that after propellant evaporation, releases the active drug in the upper respiratory tract. Owing to its small diameter size, about 10% of the drug reaches the bronchopulmonary tract and provides therapeutic activity.

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FORMULATIONS, PRODUCTION AND EVALUATION OF HARD AND SOFT GELATIN CAPSULES

Capsule:

Capsule Capsule is the most versatile of all dosage forms. Capsules are solid dosage forms in which one or more medicinal and inert ingredients are enclosed in a small shell or container usually made of gelatin. There are two types of capsules, “hard” and “soft”. The hard capsule is also called “two piece” as it consists of two pieces in the form of small cylinders closed at one end, the shorter piece is called the “cap” which fits over the open end of the longer piece, called the “body”. The soft gelatin capsule is also called as “one piece”. Capsules are available in many sizes to provide dosing flexibility. Capsules are available in many different sizes and shapes and can be used for the administration of powders, semisolids and liquids.

Advantages of Capsules:

Advantages of Capsules • Capsules mask the taste and odor of unpleasant drugs and can be easily administered. • They are attractive in appearance • They are slippery when moist and, hence, easy to swallow with a draught of water. • As compared to tablets less adjuncts are required. • The shells are physiologically inert and easily and quickly digested in the gastrointestinal tract. • They are economical • They are easy to handle and carry. • The shells can be opacified (with titanium dioxide) or colored, to give protection from light.

Disadvantages of Capsules:

Disadvantages of Capsules • The drugs which are hygroscopic absorb water from the capsule shell making it brittle and hence are not suitable for filling into capsules. • The concentrated solutions which require previous dilution are unsuitable for capsules because if administered as such lead to irritation of stomach.

Method of production of empty hard gelatin shells::

Method of production of empty hard gelatin shells: The metal moulds at room temperature are dipped into a hot gelatin solution, which gels to form a film. This is dried, cut to length, removed from the moulds and the two parts are joined together, these processes are carried out as a continuous process in large machines. The completely automatic machine most commonly used for capsule production consists of mechanisms for automatically dipping, spinning, drying, stripping, trimming, and joining the capsules.

Capsule shell filling :

Capsule shell filling Hand operated hard gelatin capsule filling machines – hand operated and electrically operated machines are in practice for filling the capsules but for small and quick dispensing hand operated machines are quite economical.

Industrial scale filling:

Industrial scale filling The machines for industrial -scale filling of hard gelatin capsules come in great variety of shapes and sizes, varying from semi- to fully automatic and ranging in output from 5000 to 15000 per hour. Automatic machines can be either continuous in motion, like a rotary tablet press, or intermittent, where the machine stops to perform a function and then indexes round to the next position to repeat the operation on a further set of capsules.

Types of excipients used in powder-filled capsules :

Types of excipients used in powder-filled capsules • Diluents – diluents are the excipients that are usually present in the greatest concentration in a formulation and they make up the necessary bulk when the quantity of the active ingredient is insufficient to make up the required bulk eg . Lactose, maize starch, calcium sulfate etc. • Lubricants and Glidants – which reduce powder to metal adhesion and promote flow properties eg . Magnesium stearate , talc. • Wetting agents – which improve water penetration for poorly soluble drugs eg . Sodium lauryl sulfate • Disintegrants – which produce disruption of the powder mass crospovidone , sodium starch glycolate .

Difficulties in filling capsules :

Difficulties in filling capsules Deliquescent or Hygroscopic powders – a gelatin capsule contain water which is extracted or taken up by a hygroscopic drug and renders the capsule very brittle which leads to cracking of the capsule. The addition of an adsorbent like magnesium carbonate, heavy magnesium oxide or light magnesium oxide overcomes this difficulty provided the capsules are packed in tightly closed glass capsule vials. Certain substances when mixed together tend to liquefy and form a pasty mass due to the formation of a mixture which has a lower melting point than room temperature. - Eutectic mixture s The absorbents used are magnesium oxide and kaolin. Another method in dealing with such type of difficulty is that the substances are mixed together so as to form a eutectic mixture, then an absorbent like magnesium carbonate or kaolin is added.

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3. Addition of inert powders – when the quantity of the drug to be filled in capsules is very small and it is not possible to fill this much small amount in capsules then inert substance or a diluent is added so as to increase the bulk of the powder, which can be filled easily in capsules. 4. Use of two capsules – some of the manufacturers separate the incompatible ingredients of the formulation by placing one of the ingredients in smaller capsule, and then placing this smaller capsule in a larger capsule containing the other ingredients of the formulation. Some powders which lack adhesiveness and most granular powders are difficult to fill in the capsules by punch method because they are not compressible and flow out of the capsule as soon as they are lifted from the pile of powder into which they are punched. To overcome this difficulty the non-adhesive powders should be moistened with alcohol and the granular powders should be reduced to powder before filling into capsules.

Soft gelatin capsules :

Soft gelatin capsules A soft gel (a soft gelatin capsule) is a solid capsule (outer shell) surrounding a liquid or semi-solid center (inner fill). An active ingredient can be incorporated into the outer shell, the inner fill, or both.

Advantages of soft gelatin capsules:

Advantages of soft gelatin capsules The bioavailability of hydrophobic drugs can be significantly increased when formulated into soft gelatin capsules. Many problems associated with tableting, including poor compaction and lack of content or weight uniformity, can be eliminated when a drug is incorporated into this dosage form. Improved stability of drugs that are highly susceptible to oxidation can be achieved when formulated into a soft gelatin capsule.

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Disadvantages of soft gel capsules: 1. Requires special manufacturing equipment 2. Stability concerns with highly water soluble compounds, and compounds susceptible to hydrolysis 3. Limited choices of excipients/carriers compatible with the gelatin

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Gelatin soft capsules are made from gelatin and water but with the addition of a polyhydic alcohol, such as glycerol or sorbitol, to make them flexible. Sorbitol is less hygroscopic than glycerol. They usually contain a preservative, such as beta-naphthol. They are available in variety of shapes and sizes • Spherical – 0.05 -5 ml • Ovoid – 0.05 - 7 ml • Cylindrical – 0.15- 25 ml • Tubes – 0.5 - 10 ml • Pear shaped – 0.3 - 5ml They are most suitable for liquids and semisolids and are widely used, in spherical and ovoid forms for vitamin preparations such as cod liver oil, vitamins A and D and multiple vitamins.

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Rotary machines are capable of producing between 25000 and 30000 capsules an hour

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Formulation of soft gelatin capsules Gelatin shell formulation: Typical soft gels are made up of gelatin, Plasticizer – usually 20-30% of glycerol, sorbitol and propylene glycol. Water - 30-40 % of the wet gel formulation and 5-8% w/w of dried state. and materials that impart the desired appearance Colorants - soluble dyes, or insoluble pigments or lakes and/or Opacifiers - titanium dioxide ), and sometimes flavors. Quality control of capsules 1. Shape and size 2. Color 3. Thickness of capsule shell 4. Leaking test for semi-solid and liquid ingredients from soft capsules 5. Disintegration tests 6. Weight variation test 7. Percentage of medicament test

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BASE ADSORPTION OF SOLIDS TO BE SUSPENDED IN SOFT GELATIN CAPSULES Base adsorption is expressed as the number of grams of liquid base required to produce a capsulatable mixture when mixed with one gram of solid(s). The base adsorption of a solid is influenced by such factors such as the solids particle size and shape, its physical state (fibrous, amorphous, or crystalline), its density, its moisture content, and its oleophilic or hydrophilic nature. The base adsorption is obtained by means of the following formula – Weight of the base/ Weight of the solid = Base Adsorption The base adsorption is used to determine the “minim per gram” factor (M/g) of the solid(s). the minim per gram factor is the volume in minims that is occupied by one gram (S) of the solid plus the weight of the liquid base (BA) required to make a capsulatable mixture.

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The minim per gram 17 factor is calculated by dividing the weight of the base plus the gram of solid base (BA+ S) by the weight of the mixture (W) per cubic centimeter or 16.23 minims (V). A convenient formula is- (BA + S) x V/ W = M/g Thus lower the base adsorption of the solid (s) and higher the density of the mixture, the smaller the capsule will be.

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Example of suspension fills include drug suspended in the following carriers: 1. Oily mixtures: a) Soybean Oil with beeswax (4-10% w/w) and lecithin (2-4% w/w). The lecithin improves material flow, and imparts some lubrication during filling. Add enough beeswax to get a good suspension, but avoid creating a non-dispersible plug. b) Gelified Oil (e.g. Geloil® SC), a ready to use system composed of soybean oil, a suspending agent, and a wetting agent. 2. Polyethylene glycol • PEG 800 -1000 for semi-solid fills • PEG 10,000 -100,000 for solid fills • Or mixtures of the above. (Heat up to 35ºC to make fluid enough for filling) Optional Ingredients that can be added in the suspension fill: • Surfactant: sorbitan derivatives such as polysorbate 80 or lecithin. • For hydrophobic drugs dissolved or dispersed in an oily matrix, a surfactant of HLB 10 will increase the dispersibility of the product in aqueous fluids and also may improve bioavailability.

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Effect of Temperature and Humidity on Capsule shell Temperature Humidity Effect on Capsule shell 21-24°C 60% Capsules become softer,tackier and bloated Greater than 24°C Greater than 45% More rapid and pronounced effects – unprotected capsules melt and fuse together

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Recent updates in Capsule technology New products by Capsugel : 1. Oceancaps capsules made from all natural fish gelatin derived from farm-raised fish, they have the same characteristics as traditional gelatin capsules, including appearance, chemical stability, and versatility. Plus, they are odorless and tasteless Licaps new 000 size capsules are ideal for maximizing liquid dosage with a fill capacity of 1000mg to 1400mg depending on the density of the liquid fill material. This two-piece capsules has been specially designed to be sealed for secure containment of liquids and semi-solids without banding. Available in both gelatin and HPMC ( Hydroxypropyl Methylcellulose) capsules.

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B) New product by Natco Pharma LUKATRET (Tretinoin - all trans retinoic acid) available in the form of 10 mg. capsules (in a pack of 100 capsules) is used in the treatment of Acute Promyelocytic Leukemia (APL) C) New products by Banner Pharmacaps Inc. Enteric Softgel called Entericare, with enteric properties built into the shell matrix of the capsules for delivering very potent (small quantities) as well as drugs that require larger quantities and provide sustained delivery for more than an 8- to 12-hour period. D) New product by Shionogi Qualicaps First HPMC capsule developed for eventual use in pharmaceutical products.

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References Pharmaceutics – The Science of Dosage form Design by M.E. Aulton , 2 nd Edition. Remington – The Science and Practice of Pharmacy, 20 th Edition, Volume – 1. The Theory and Practice of Industrial Pharmacy by Leon Lachman . Encycloprdia of Pharmaceutical Technology, Volume – 2. Textbook of Pharmaceutics by Bentley, 8 th Edition. Modern Pharmaceutics by Gilbert S. Bankers, 4 th Edition, Dekker series. Website – www.capsugel.com Website – www.liquidcapsules.com Pharmabiz.com: Hard gelatin packs for liquids, May 12, 2005. Suggested Reading Leon Lachman . The Theory and Practice of Industrial Pharmacy

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