Capsule Components

• Capsules are small packages designed for oral use
• Capsules are made of gelatin or other suitable materials
• They contain medicines to produce a unit dosage
• Hard capsules have two cylinder shaped pieces that are closed at one end

Capsule Components

• Hard and soft capsules contain gelatin, water, and colorants
• They also contain optional materials like process aids and preservatives
• Soft capsules contain plasticizers like glycerin and sorbitol
• Gelatin is a material derived from collagen which is a natural protein
• Raw materials for collagen are animal skin and bones
• Gelatin is non-toxic and readily soluble in biological fluids at body temperature
• Gelatin is mobile as a solution of high concentration up to 40% at 50°C
• Gelatin as a solution in water undergoes a reversible change from sol to gel
• Two types of colorants are used: water soluble dyes and insoluble pigments
• Dyes and pigments are mixed together as solutions or suspensions
• Common dyes are erythrosine, indigo carmine, and quinoline yellow
• Pigments include iron oxide (black, red, and yellow) and titanium dioxide (white)
• Sodium laurylsulfate (0.15%) is used as a wetting agent
• Preservatives prevent microbiological contamination during manufacture
• Moisture levels of 13-16% in finished capsules prevent bacterial growth

Manufacture

• Metal moulds at room T° are dipped into a hot gelatin solution which will then gel to form a film
• This is dried, cut to length, removed from the moulds and the two parts are joined
• Raw material preparation involves creating a concentrated gelatine solution
• This is followed by putting it into suitable containers
• Dyes & pigments are then added, viscosity is then adjusted using hot water
• Finally this is put inside a heated holding hopper
• Manufacturing machines are housed in rooms where humidity and T° are closely controlled
• Capsules must be packed for shipment in moisture-proof liners
• Heat-sealed aluminium bags in cardboard cartons are the preferred containers
• Capsules may become brittle at high temperatures and gain moisture and soften at high humidity

Capsule Filling

• Capsule fill weight for a powder can be estimated by multiplying the body volume by its tapped bulk density
• Excipients mixing and capsules filling are the two steps for the capsule filling process
• Capsules contents may be powders, granules [(un)coated], pellets [(un)coated], or mini tablets
• The excipients mixing process should present better flow properties for a regular filling volume.
• Pharmaceutical mortars are used at pharmacy level, while mixing machines are used at industrial level
• Homogeneity of the mixture depends on physical characteristics of powders
• It also depends on mixing intensity, mixing time, and proportions of powders to be mixed
• Industry capsule filler ingredients include ingredients A, B, C, D, and E (lubricant)
• Milling/sieving, blending, capsule cleaning/dedusting, and capsule inspection is required
• The capsule then goes through a check-weighing system, rejects the bad capsules, and packages the accepted
• Lab steps include the placement of empty capsules, capsules opening, capsules filling, capsules verification, and capsules closure
• Automatic filling machines are comparable to rotary tablets presses

Capsule Filling Machine Types

• For powder formulations, plastic plates with holes to take from 30 to 100 capsules of a specific size are used at hospitals
• Empty capsules are fed into a hole and powder is placed onto the surface of the body plate
• This is then spread using a spatula so the bodies are filled and good flow properties are necessary for uniformity of weight
• Industrial scale filling machines are varied in shape and size offering outputs of 5000 to 150000 per hour
• Based on a chamber with a volume that can be changed, pellet filling uses machines adapted from powder use on an industrial scale
• Pellets are modified-release patterns as granules or coated pellets
• Pellets are not compressed, and are held inside measuring devices by mechanical means
• For tablet filling, tablets are placed in hoppers and fall down tubes
• At the bottom, a gate device will allow a set number of tablets to pass

Formulation Requirements

• Formulations require uniform filling for a stable product
• They must release their active content in a form available for absorption by the patient
• They need to comply with pharmacopoial requirements like dissolution tests
• The majority of capsule filling products are formulated as powders
• The properties may be governed by excipients or by active ingredients, depending on concentration in the powder
• Good flow relies on using free flowing diluent and glidant
• No adhesion relies on using a lubricant, and cohesion relies on using a plug forming diluent

Formulation For Release

• A formulation for the release of active ingredients involves the disintegration of the capsule shell
• The contents must start to empty out before all the gelatine dissolves
• The rate controlling of disintegration and product release depends on the formulation of contents
• Particle size, and the use of hydrophilic and dispersible compounds affect this as does how well the fluid can penetrate in the mass
• Diluents, as the greatest excipients in formulations, can play a role in drug release
• A soluble diluent like lactose may make the powder mass more hydrophilic
• Lubricants and glidants may have influence on drug release
• To avoid this, make mass more hydrophobic

Formulation Optimization

• Formulation Optimization provides a product that complies with uniformity of filling weight and content
• This will also ensure disintegration, and dissolution rate
• Summarized: active ingredient has an optimum particle size
• Hydrophilic mass will relate to solubility of active excipients
• It includes dissolutions aids, wetting agents, super-disintegrants
• Optimum formulation for filling and release

Soft Gelatin Capsules

• Soft gelatin capsules (softgels) are capsules that consist of liquid or semi-solid matrix encased inside a one-piece outer gelatine shell
• Solid ingredients at room temperature can be encapsulated into softgels if they are at least semi-solid below approximately 45°C
• Drug compounds can be solutions or suspensions in the capsule fill matrix which may be hydrophilic or lipophilic
• The matrix may be a mixture of both hydrophilic and lipophilic ingredients in some formulations
• Softgel capsule shells contain gelatin, water, and plasticizers and may be transparent or opaque, colored and flavored
• Soft gels improve drug absorption, mainly for poorly water-soluble drugs
• They have better patient compliance and consumer preference: they are easy to swallow
• They also have a convenient liquid-drug dosage form and avoids dust-handling problems during dosage form manufacture
• It is safer for potent and cytotoxic drugs providing better operator safety and environmental controls
• They overcome manufacture problems of compressed tablet or hard-shell capsules as oils and low melting point drugs
• Liquid flow provides more precise dosage uniformity for low-dose drugs than powder flow
• Drug solutions provide better homogeneity than powder or granule mixtures
• Drugs are protected against oxidative degradation by lipid vehicles and softgel capsule shells this product

Soft Gelatin Capsule Defenition and Advantages

• A soft gelatine capsule is a solid oral dosage form in which 1 or 2 medicines are dissolved in a single soft elastic gelatine shell
• Gelatine, water, glycerine, sorbitol or propylene glycol are mixed to prepare to make the capsules flexible
• A preservative is usually added to prevent bacteria and fungi growth
• Advantages include its soft, elastic and flexible nature
• The liquid nature of the fills allows rapid release of their content with potential enhanced bioavailability
• Dosage forms is uniquely suited for liquids and volatile drugs
• It is elegant, easy to swallow, can have its unpleasant taste masked and comes in various shapes
• It can provide immediate or delayed drug delivery and provides unit dose delivery

Soft Gelatin Capsule Disadvantages

• It requires the necessary filling equipment and experts
• Additional quality control measures may also be required as it is generally expensive
• Highly water soluble compounds cannot be encapsulated as the compound is susceptible to hydrolysis
• There are limited choices of excipients compatible with the gelatine
• It contains a shell of gelatin plasticizer and water, and a fill solution or suspension of drug, water or oil miscible vehicle
• Twist-off softgels are designed with a tag to be twisted or snipped off
• This enables allows for easy access to the fill material
• Making this useful for unit dosing of dosing of topical medication, inhalation, or dosing of a paediatric product
• Meltable softgels are designed as 'patient-friendly' pessaries or suppositories
• Oral dosage form of ethical or proprietary products for human or veterinary use
• Suppository dosage form for vaginal and rectal use
• Rectal dosage forms are more acceptable for pediatric and geriatric use

Manufacturing Softgels

• A small sack of gelatin is filled with medication, and heat sealed
• The method was improved by sealing 2 sheets of gelatine film between a pair of matching flat brass dies
• Each die contained pockets where the gelatin sheet was pressed and medication was put inside
• With the invention of the rotary die encapsulation machine, liquid fill capsules may be produced on a production scale
• This enables continuous formation of a heat between 2 ribbons of gelatine along with simultaneous dosing of the fill liquid into each capsule
• Carried out simultaneously, the process deals with gel mass which provide the softgel shell
• Additionally, it deals with process for the the fill matrix for the softgel contents
• During semi-solid and liquid filling, liquids are dosed into capsules using volumetric pumps
• The problem after filling is to stop leakage from the closed capsule
• This is done either by by formulation or by sealing the capsule
• Semi-solid are formulations solid at ambient T° and liquefied for filling (heating or stirring) with melting point higher than 35°C
• For non aqueous liquids mobile at ambient T°, the capsules require sealing after filling
• It requires temperature generating heat for capsule seal formation
• It require the timing of dosing of unit quantities of fill matrix into capsule and pressure exerted between 2 rotary dies

Formulation Of Softgels

• Softgel shells should have good barrier against oxygen diffusion, determining its permeability coefficient
• Biphasic dosage form, solid-phase and liquid-phase capsule matrix, lipophilic liquids/oils, or hydrophilic liquids
• Can also come in self-emulsifying oils, microemulsion and nanoemulsion, or suspensions
• Triglycerides oils, such as soja bean oils, are commonly used as Lipophilic liquids or oils
• Active ingredients like hydroxycholecalciferol, vitamin D analogues, and steroids can be formulated into oil solutions for encapsulation
• Polar liquids with high molecular weight like PEG are what hydrophilic liquids are made of
• A formulation of pharmaceutical oil and a non-ionic surfactant makes self-emulsifying oils
• This provides an oily formulation which disperse rapidly in GI fluid, and provide rapid transfer of drug to the absorption mucosa
• Lipid-surfactant-polar liquid system is used for microemulsion and nanoemulsion systems
• Translucide single phase appearance, nonoemulsion → droplet size is about 100 nm with high capacity to solubilize drugs

Lipolysis

• Result of Lipolylis results in the action of a enzyme pancreatic lipase on triglycerides and partial gycerides
• It forms di-monoglycerides and fatty acids known as lipophilic products and interact with bile salts by turning forming small droplets or vesicles
• These are then broken down into smaller and smaller vesicles in micelles of 3-10nm size
• The process of lipolysis promotes the formation of an excellent dissolution medium for the drug
• Drug compounds with a high solubility in lipolytic products compared to triglycerides are advantageous for lipolysis in intestinal lumen
• Absorption of a drug may be adversely affected by the presence of bile salts by triggering lipolysis
• Lipophilic and hydrophilic surfactants able to block or promote lipolysis may be presented in softgel fill matrix formulations

Product Quality Considerations

• Ingredients specifications must be tested to ensure compliance with pharmacopoeia specifications
• The potential impurities include aldehydes and peroxides in polyethylenglycol which may lead to insolubilization through further polymerization
• In-process testing most important tests include: gel ribbon thickness, softgel seal thickness, fill matrix weight, capsule gel weight
• It also include softegel moisture level and softgel hardness at the end of drying stage
• Finished product testing involves the assessment of capsule appearance
• Testing for the active ingredient assay, related substance assay, fill weight, content uniformity, and microbiological test

Rectal and Vaginal Drug Delivery

• Rectal route is for patients unable to make use of oral route
• This includes patients with GI tract ailments like nauseous, or vomiting, as well as unconscious patients
• Meant for drug considered less suitable for oral administration due to Gl side effects, instability in GI tract, or drug with unacceptable taste
• The rectal administration is not the route of first choice, but offers great advantages to patients producing local or systemic effects
• The rectum is part of colon forming the last 150-200mm of Gl tract
• A vehicle consists of glycerides type fatty bases and water soluble ones
• Fatty bases have a melting point lower than 37°C, melting range small enough to give rapid solidification after preparation

Suppository Characteristics

• The ideal suppository base should release the medicaments readily
• It should be compatible with a variety of drugs, melt at body temperature or disperse in the body fluids
• It should be nontoxic, nonirritating to mucous membranes, stable on storage
• It should not bind or otherwise interfere with release or absorption of drug substances
• It should be stable if heated above its melting point and be molded easily and should not adhere to the mold
• Cocoa Butter, Polyethylene Glycol, Glycerin or glycerol, Hydrogenated Vegetable Oils, and Gelatin are primary bases used

Drug Characteristics

• As a vehicle, a drug must have good solubility in the vehicle while in solution or suspension in a suppository
• The drug must have a good solubility in rectal fluid, and needs a driving force for absorption
• A drug with high vehicle-to-water partition coefficient has a tendency to stay in the vehicle → it offers slow drug release
• In this case, certain lipid solubility will required for penetration through the rectal membrane
• W/O emulsion type suppositories are strongly discouraged
• Surfactants may be added to surface properties so particles can be transferred from one phase to another
• Particle size should prevent sedimentation, it should be small to reduce irritation to the patient and high dissolution rate (50-100µm)
• Increasing the amount of drug increases of viscosity

Moulds

• Suppository and pessary moulds used in dispensaries are metal
• Typically have six to twelve cavities and can be opened longitudinally for lubrication
• You can remove the contents once it is cleaned after removing a screw
• Abrasives should never be used on the interior of the mould
• They should be immersed in hot water containing detergent and wiped gently with a soft cloth when cleaning
• Since the densities of medicaments change the displacement value is number of parts by weight of the medicament that displaces one part by weight of the base

Displacement Value Calculation

• Step I calculates the theoretical weight of total Base
• This equals No of suppositories X weight of each suppository
• Step II calculates the Theoretical weight of total drug required
• This equals No of suppositories X weight of drug in each suppository
• Step III adds the calculated weight of calculated theoretical base (step 1) with the calculated weight of theoretical drug (step II)
• This returns the theoretical weight of total suppositories
• Step IV involves measuring the Practical Weight of the total suppositories
• Step V is the difference in weight between the results of Step III-Step IV returning the theoretical weight of total suppositories - Practical Weight of total suppositories
• Step VI returns the Displacement value and equals (Step II/ Step V) Theoretical weight of total drug/Difference in total weight of suppositories

Lubrication of Mould

• A lubricant must differ in composition from the suppository base
• A lubricant also needs to provide a buffer film between the suppository and the metal while not being absorbed
• For theobroma oil suppositories, an oily lubricant is useless
• After lubrication, the mould is closed and inverted on a clean white tile to drain

Manufacturing and Quality Control

• Melting the vehicle, mixing the drug and molten vehicle, dispensing in moulds, and cooling to solidify occurs during manufacture
• Similar on both small and automatic scales, most suppositories are packed individually in PVC or aluminium foil pack
• Appearance, weight uniformity, disintegration, melting, (dissolution) behaviour is required for Quality control
• Must include mechanical strength, content of active ingredients, and drug release, to ensure the success of optimum bioavailability
• 37°C is the set temperature to be used with a focus on the viscosity at this T° and focus on the contact area in the rectum
• Release medium should use of membranes testers
• Treatment of local disturbances like hemorrhoids fatty ointments. is effective.

Rectal and Vaginal Drug Delivery

• Rectal formulations besides suppositories is the local treatment of hemorrhoids.
• Tablets, capsules, and microenemas are used for systemic administration.
• Three release mechanisms are melting, speading sedimentation, wetting and dissolution
• Factors influencing these release mechanisms are the quantity of fluid available, the properties of rectal mucus, the motility of the rectal wall
• Other factors include the solubility in water and vehicle of drug, properties of drug, particle size and the amount of the drug.
• Drug is administered via the vaginal for local effects of e.g. cases of trichomonas and candida infections
• Higher bioavailability compared to oral route, drugs enter immediately into the systemic circulation without passing through the metabolizing liver

Pessaries

• Solid medicament that introduces medication into the vagina: they melt or dissolve and exert a local action
• Moulded pessaries and compressed pessaries are the 2 types that are cone-shaped are prepared in a similar way to suppositories
• Tablets prepared by compression, are made in variety of shapes
• Treats vaginitis (inflammation of the vagina) and leucorrhea (unpleasant vaginal discharge).
• Acetarsol (an antiprotozoal agent), Di-iodohydroquinolone (for yeast and protozoal infections) is used as medicaments
• Others are Lactic acid (often used in leucorrhea), Nystatin (for yeast infections), and Crystal violet and hydrargaphen (for various microbial infections).
• Vaginal fluid is moist by a surface film of cervical mucus and exfoliated cells from the vagina itself.
• The Vaginal film consists of transudation from the blood vessels through the intercellular channels to the lumen

Formulations for Vaginal Dose

• A large variety of dosages like : tablets, capsules, pessaries, solutions, sprays, foam, creams, and ointments.
• Additives are used to improve the disintegration of vaginal tablets utilizing bicarbonate with organic acid for CO2,
• Vaginal tablets fillers is typically lactose, and Vaginal suppositories are mostly prepared with glycerol-gelatin bases
• PEGs can cause irritation, and Fatty excipients are not very much use.
• As a result, drug delivery forms demand auxiliary device to obtain deep insertion of dosage form