PR5217 Formulation Science PDF

PR5217 Formulation Science L09. Solid Oral Dosage Form III DUN JIANGNAN, Ph.D. AY24/25.S1 7-NOV-2024 Learning Outcomes Appreciate the capsules (hard and soft) as an important solid oral dosage form. Understanding the typical components in both hard and soft capsules, and...

PR5217 Formulation Science L09. Solid Oral Dosage Form III DUN JIANGNAN, Ph.D. AY24/25.S1 7-NOV-2024 Learning Outcomes Appreciate the capsules (hard and soft) as an important solid oral dosage form. Understanding the typical components in both hard and soft capsules, and their important properties. Understanding the formulation considirations in both hard and soft capsules.  Pharmaceutical Capsules The word ‘capsule’ is derived from the Latin capsula, meaning a small box. In current English usage it is applied to many di erent objects, ranging from owers to spacecraft. Solid dosage forms in which medicinal agents and/or inactive substances are enclosed in a small shell (usually made of gelatin) Soft capsules (Softgels) Hard capsule consists of a continuous gelatin shell consists of a cap and a body, where the surrounding a liquid, suspension or paste body fit into the cap “One-piece” “Two-piece” h ps://basicmedicalkey.com/so -capsules/ h ps://www.saintytec.com/hard-gela n-capsules/ tt tt ff ft ti fl Hard Capsules Hard capsules are a popular solid oral dosage form consisting of two pieces, a cap and body. Good patient adherence is achieved through the use of colour for identi cation, an easy to swallow shape and a shell that masks the taste of the contents fi  Raw Materials (Shells) Gelatin is the major component used for hard capsule shells, but many new products, particularly those used in dry powder inhalers, are made from hypromellose. All polymer systems need to have the same basic properties for the manufacture of capsules: Readily soluble in Non-toxic Good lm-forming materials biological uids Gelatin is a substance of natural origin that does not occur as such in nature. It is prepared by the hydrolysis of collagen, which is the main protein constituent of connective tissues. (Type A and B) Hypromellose is manufactured from cotton linters or wood by treatment with sodium hydroxide solutions and further chemicals to produce methyl hydroxypropyl ethers. These are treated with hydrochloric acid to produce di erent viscosity grades fi fl ff  Capsule sizes Hard capsules are made in a range of sizes; the standard industrial ones in use today for human medicines range in size from 0 to 4. To estimate the ll weight for a powder, the simplest way is to multiply the body volume by its tapped bulk density. The ll weight for liquids is calculated by multiplying the speci c gravity of the liquid by the capsule body volume multiplied by 0.9 (prevent over lling and spillage of liquid during machine movement) “Elongated sizes” 10% more compared with the regular sizes. fi fi fi fi Bulk Density and Tapped Density V0 Vf Bulk density = Weight / V0 Tapped density = Weight / Vf The change in packing volume occurs when void space diminishes and consolidation occurs  Capsule Shell Filling Hard capsules can be lled with a large variety of materials of di erent physicochemical properties. Gelatin and hypromellose are relatively inert materials. The substances to be avoided are those which are known to react with gelatin, e.g. formaldehyde, which causes a cross-linking reaction that makes the capsule insoluble, or those that interfere with the integrity of the shells, e.g. substances containing free water, which can be absorbed by the gelatin or hypromellose, causing them to soften and distort. There is also a limitation on the size of capsule that can be easily swallowed, and thus large doses of low-density formulations cannot be used. ff fi Formulation Considerations in Hard Capsules They must be capable of being lled uniformly (good ow and packing) to give a stable (API) product. They must release their active contents in a form that is available for absorption by the patient. They must comply with the requirements of the pharmacopoeial and regulatory authorities, e.g. dissolution tests. Powder formulation Most products that are used to ll capsules are formulated as powders Mixtures of the API together with a combination of di erent types of excipients Excipient selection is based on both API property and the capsule size! fi fi ff fl Formulation for filling Powders Hygroscopicity Flowability Particle size distribuition Bulk/tapped density Adhesion/cohesion The factor that contributes most to the uniform lling of capsules is good powder ow, because all machines operate by measuring volumes of powders. fi fl  Flow Behaviors Erratic ow Funnel ow Mass ow Rathole Arch First in, Last out ow sequence First in, First out ow sequence Worsened segregation Reduced segregation A result of alternating occurrences between an arch and a rathole fl fl fl fl fl Carr Index and Hausner Ratio Based on the density of powder: Bulk density, Tapped density Predict the propensity of a given powder to be compressed, and re ect the importance of interparticulate interactions. For a more free- owing powder, the di erence between bulk and tapped densities will be less. For a poorer owing materials, a larger di erence between bulk and tapped densities is expected. Bulk volume > Tapped volume Bulk density < Tapped density fl fl ff ff fl  Formulation for Release of API The rst stage in release from capsules is disintegration of the capsule shell. When gelatin capsules are placed in a suitable liquid at body temperature, 37 °C, they start to dissolve and within 1 minute the shell will break. With a properly formulated product, the contents will start to empty out before all the gelatin has dissolved (C). Hypromellose capsules take a longer time to the rst break, but after this tend to disperse faster than gelatin capsules. fi fi  Effects of d50 (fills) on the Rate of Absorption 3 di erent particle sizes were lled into capsules and administered to dogs: Smallest particles gave the highest peak blood level. This can be explained simply by the fact that the dissolution rate is directly proportional to the surface area of the particles: the smaller the particle, the greater the relative surface area. Sul soxazole Any negative impacts on small particle size? Aggregation fi ff fi Effects of Diluents on the Rate of Absorption Diluent is thought to be inactive material. Case: (Australia, 1960S) The diluent used was changed from calcium sulfate to lactose. In the months following this change, there was an upsurge in reports of side e ects similar to overdosing of product. It was demonstrated that the change had had a signi cant e ect on the bioavailability of the API. The change to lactose gave much higher blood levels of Why? the drug, which was probably due to it being readily soluble whereas calcium sulfate is not. ff fi ff Effects of Lubricants on the Rate of Dissolution The important thing to avoid in formulation is materials that tend to make the mass more hydrophobic. A commonly used lubricant, MgSt, unfortunately, is Chlordiazepoxide hydrophobic in nature. Dissolution rate was greatly reduced at the highest level of magnesium stearate, which they explained was due to the poor wetting of the powder mass What can you do? Alternative more hydrophilic lubricants Formulation for Position of Release Many products are formulated to release their contents in the stomach. However, this may not always be the best place for the absorption of the API, and capsule formulation can be readily manipulated so that the contents are released at various positions along the GI tract. Lower GI tract (distal), such as small intestine (huge SA), is a preferred places for absorption of most APIs. How to make the capsules “hold” the API and release it only at this location? Formulation for Position of Release Enteric coating Colpermin is an enteric-coated capsule lled with a prolonged-release formulation of peppermint oil. The capsule disintegrates in the duodenum and the contents slowly release the peppermint oil, which acts as a smooth muscle relaxant as it passes through the remainder of the tract. Products have also been prepared that have been coated with polymers that are soluble only at higher pH values, 6–7. This pH is not reached until further along the small intestine, and so the contents are delivered to the more distal parts. fi Formulation for Position of Release Many new therapeutic entities are proteins or polypeptides, and to make an e ective Modifying the lls oral dosage form, it is necessary to deliver them to the colon, thereby avoiding the proteolytic enzymes in the stomach and small intestine. EUDRATEC® COL is a pH-dependent, sustained release technology that facilitates the precise delivery of an API along the colon. The proprietary system consists of an outer layer of an enteric polymer and an inner layer of a sustained release polymer. This multi-layer combination creates a range of formulation opportunities to improve drug ef cacy. fi fi ff Softgels Softgels comprise a liquid or semisolid preparation inside a capsule that is formed in a single-step encapsulation process. Why Softgels? Bring drugs in solution (liquid dosage form) to a solid dosage form. 40% 90% Approved drugs DS under pipelines Poorly water soluble Poorly BA Different Softgels Formulations Gelatin + water + What is the shell? Plasticizer … What is inside the shell? Many things… Recent advances in the filling matrix Self-emulsifying microemulsions and nanoemulsions encapsulated as preconcentrates in softgels. Lipophilic + hydrophilic + surfactant -> disperses after oral administration to form an emulsion  Softgels Drug Delivery Systems Meltable softgels Suckable softgels Orally administered softgels Chewable softgels Twist-off softgels Highly avoured shell is chewed to Easy-to-swallow Topical use release the drug liquid ll matrix. fl fi Key Features and Advantages of Softgels **Compared with tablets More costly than tablet formulations and require specialized manufacturing equipment Softgels Improves the BA PK of softgels and tablets containing 400 mg PK comparing a softgel nanoemulsion formulation of progesterone with ibuprofen (in 12 volunteers) a softgel containing a suspension of the drug in an oil following single dose administration in 12 healthy human volunteers Saano et al., 1991 Ferdinando, 2000  Formulation of Softgels Shells Typical softgel shells are made up of gelatin, a plasticizer and materials that impart Shell formulation the desired appearance (colourants and/or opaci ers) and sometimes avours. A large number of di erent gelatin shell formulations are available depending on the nature of the Gelatin (~40%) liquid ll matrix. Most commonly, the gelatin is base-processed type B gelatin (high viscosity). To make the softgel shell elastic and pliable. Glycerol is the most commonly used one, Plasticizers (~20-30%) followed by sorbitol and propylene glycol. Compatibility with the ll formulation! ~30-40% before encapsulation to ensure proper processing during gel preparation; In dry softgels, the Water equilibrium water content is typically in the range of 5% to 8% w/w (water that is bound to the gelatin in the softgel shell). Although not absolutely impossible, API is usuallly not presented in the Softgels shells. Rather, API is included in the ll matrix. fi fi ff fi fi fl  Properties of Softgels Shells The gelatin shell of a soft gelatin capsule provides a good barrier against the Oxygen permeability di usion of oxygen into the contents of the product. The permeability coe cient (P) is related to the di usion coe cient (D) and the solubility coe cient (S) by the equation P = DS. The oxygen permeability decreases with the RH and the glycerol content in the gelatin shell formulation. For maximum protection against the ingress of oxygen, the gelatin shell should be dry and formulated to contain approximately 30% to 40% glycerol. ff ffi ff ffi ffi  Properties of Softgels Shells Softgels contain little residual water, and compounds which are susceptible to Residue water content hydrolysis may be protected if they are dissolved or dispersed in an oily liquid ll material. The minimum water content (~7% @ 31% RH) is found at glycerol levels in the shell of between 30% and 40%. The residual water content of most pharmaceutical compounds stored at 20% relative humidity is low and the water levels in the lls of softgels therefore are very low. fi fi Formulation of Softgel Fill Materials The liquid-phase ll matrix is selected from components with a wide range of di erent physicochemical properties. The choice of components is made according to one or more of a number of criteria, including the following: Capacity to dissolve the drug (if a solution ll is required); Rate of dispersion in the gastrointestinal tract after the softgel shell ruptures and releases the ll matrix; Capacity to retain the drug in solution in the gastrointestinal uid; Compatibility with the softgel shell; and Ability to optimize the rate, extent and consistency of drug absorption. fi fi fl ff fi Types of Softgels Fill Matrices Lipophilic liquids/oils Trigylceride oils, such as soya bean oil, are commonly used in softgels (limited solubility) Hydroxycholecalciferol and other vitamin D analogues and steroids such as oestradiol can be formulated into simple oily solutions for encapsulation in softgels. The drug may also be suspended in oils with appropriate excipients to ensure homogeneity during the manufacturing process. Types of Softgels Fill Matrices Polar liquids with a su ciently high molecular weight are commonly used in softgel Hydrophilic liquids formulation either to dissolve or to suspend the drug. Polyethylene glycol (PEG) is the most frequently used, for example PEG 400. Smaller hydrophilic molecules, such as ethanol or indeed water, can be incorporated in the softgel ll matrix in low levels, typically below 10% by weight. Because of the potential issue on physical instability as they can migrate into the shell ffi fi  Types of Softgels Fill Matrices Self-emulsifying drug delivery systems (SEDDS) Improved pharmacokinetic characteristics A combination of an oil and a surfactant can provide a formulation which emulsi es and disperses rapidly in the GI uid. The resulting droplets enable rapid transfer of the drug to the mucosa and subsequent drug absorption. If the droplets formed on contact with aqueous media are in the micrometre size range, then the emulsion formed is known as a microemulsion; if they are in the nanometre range, then it is known as a nanoemulsion. In order to produce a microemulsion or a nanoemulsion in the GI tract, a ‘preconcentrate’ is formulated in the softgel ll matrix. The preconcentrate ll matrix contains a lipid component and one or more surfactants, which spontaneously form a microemulsion or a nanoemulsion on dilution in GI uid. fl fi fl fi fi End of the Session