Technical problems High weight and dose variation Capping and lamination Low mechanical strength Adhesion and sticking to punches

Capping Lamination

Chipping Breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operations. Due to : Incorrect machine settings, specially mis-set ejection take-off.

Reasons for capping and lamination 1-- air–entrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die. 2-- Light granulations or large amount of fines (Fluffy material may become more dense be increase the amount of binder) (Remove some or all fines through 100 to 200 mesh screen or change speed of grinding (

3-- Deep concave punches or beveled-edge faces of punches which gradually curve inward with use and form “claw” that pull off the crowns of tablets Use flat punches. 4-- Increase the radius of the curvature of the punch face (lead to increase compression force at the edges more the tablet center

6 -- Careless in setting up the press lead to lower punch remains below the face of die during ejection so the sweep-off blade cuts the tablets and leave the bottom in the die Make proper setting of lower punch during ejection Adjust sweep-off blade correctly to facilitate proper ejection.

Sticking Refers to the tablet material adhering to the die wall. Granules not dried properly. Too soft or weak granules. Too much binder Hygroscopic granular material. Too little pressure. Compressing too fast.

Methods to overcome picking and sticking problems Design lettering as large as possible. Plate the punch faces with chromium to produce a smooth and non-adherent face. Increase lubrication; use colloidal silica as a ‘polishing agent’, so that material does not cling to punch faces. Reduce the amount of binder or use a different type of binder. Dry the granules properly. Make moisture analysis to determine limits. Increase pressure to optimum.

Mottling Term used to describe an unequal distribution of colour on a tablet, with light or dark spots standing out in surface. A coloured drug used along with colourless or white-coloured excipients. Migration of the dye to the surface of granules while drying. Improper mixed dye, especially during ‘Direct Compression’. Improper mixing of a colored binder solution.

Solved by Use appropriate colourants (Incorporate dry colour additive) Change the solvent system, Change the binder, Reduce drying temperature Use a smaller particle size to prevent segregation.

EVALUATION OF TABLETS

Weight variation Tablets vary in weight beyond accepted weight Due to: - variation of granules size fill the volume of the die (void spaces between filled particles) Poor flow so some dies are incompletely filled Punches variations as lower punches are of unequal lengths

Hardness variation due to volume of materials differ and the distance between punches varies

Evaluation of tablets I – Non official tests (Non – compendial standards) General appearance The general appearance of tablets, its visual identity and overall ‘elegance’ is essential for consumer acceptance, control of lot-to-lot uniformity Control of general appearance involves measurement of tablet’s size, shape, color, presence or absence of odor, taste, surface textures

Mechanical strength evaluations Are tests associated with resistance of solid specimen to fracture or attrition Tablets should be hard enough to withstand mechanical stress during packaging, shipment, and handling by the consumer.

Hardness tests/ Crushing strength/breaking strength The test measures crushing strength ; defined as the compression force applied diametrically on the tablet till breaks down. Maxm weight is determined Erweka hardness

Friability The tablet may well be subjected to a tumbling motion. For example, Coating, packaging, transport, which are not severe enough to break the tablet, but may abrade the small particle from tablet surface. To examine this, tablets are subjected to a uniform tumbling motion for specified time and weight loss is measured. (100 rpm for 5 mins) Roche friabilator is most frequently used for this purpose.

Official control tests Weight variation Content uniformity Disintegration Test : time for tablets fragmentation End point is the time at which all visible parts have been eliminated Dissolution test: measure the rate of drug dissolution in vitro that represent amount of drug ready for absorption

Dissolution mainly carried to: Evaluate the effect of formulation variables ensure that product comply with specification To indicate the performance of preparation under vivo conditions

TABLET COATING

Types of coating Sugar coating Film coating Enteric coating Compression coating Gelatin coating

Sugar coating Traditional method for tablets coating Based on successive application of sucrose-based solutions to tablets cores in suitable coating equipment (Pan coating) 1- Waterproofing and sealing of tablet cores Sealing tablets against moisture and water entry by applying water-impermeable polymer Shellac, cellulose acetate phthalate , polyvinyl acetate phthalate

Sub-coating 3-5 sub coats of sugar syrup ( for rounding the tablets and bonding the sugar coating to the compressed tablets (sub-coating may be repeated till the desired shape or size is obtained) Smoothing and final rounding Sub-coated tablets covered with 5-10 additional coat with thick syrup (85%)

Finishing and coloring For tablets smoothness and coloring several coats with thin syrup containing color Polishing To acquire an acceptable (beeswax and carnauba wax) Printing with manufacture logo or code for identification Problem Mottling or spotting (due to moisture migrates to surface)

Pan coating

Film coating Based on spraying polymer solution or suspension on to rotating mixed tablets bed, the solvent was evaporated leave a thin film of coating material. The application of coating, is additional step in the manufacturing process increases the overall processing time and cost of production.

Aqueous film coating 1-Cellulose derivatives HPMC, MC, HPC, CMC Alginate , pectin 2- Plasticizer (0.5-2%) to modify physical properties (glycerol, propylene glycol, polyethylene glycol Colorant and opacifiers 2.5-8% ( e.g iron oxide, FD lakes Vehicle = water

Non Aqueous film coating formulation Used to give modified release aspect to the final dosage form Ethyl cellulose: Cellulose acetate phthalate (CAP) used for enteric coating Dissolve only at pH above 6 , and used to delay drug release Hydroxypropyl methylcellulose phthalate (HPMCP)

Deliver the drug to intended local effect (intestinal antiseptic) Enteric coating is an outer layer applied to a tablet or pill. Protect the stomach from the irritant effect of certain drugs (sodium salicylate) Deliver the drug to intended local effect (intestinal antiseptic)

Shellac Cellulose acetate phthalate Polyvinyle acetate phthalate Soluble acrylate derivatives Hydroxypropyl methylcellulose phthalate

Role of Lubricants : F- Lubrication and blending dry lubricant is added to the granulation. So that each granule is covered with lubricant, it may be dusted over the spread-out granules or blended in a powder mixer Role of Lubricants : They improve the flow of the granulation in the hopper to the die cavity They prevent the adhesion of the tablets to the punches and dies during compression, They reduce friction between the tablet and the die wall during the tablet's ejection from the tablet machine, and they give a sheen to the finished product.

Compression coating Based on inner core (compressed tablets) Coating materials compressed onto tablets core of drug with tablet press Advantages: Coating process is anhydrous (safe drug sensitive to moisture) The coat is more uniform than the usual sugarcoating Tablets are lighter and smaller , easy to swallow and less expensive to package and skip

CAPSULES

Capsules The word capsule is derived from the Latin word capsula, meaning a small box. Capsules are solid dosage forms in which one or more medicinal and/or inert substances are enclosed with a small shell or container generally prepared from a suitable form of gelatin. There are two types of capsules, " Hard " and " Soft" ; better adjectives would be two pieces instead of hard and one- piece instead of soft

Types of Capsules Hard Gelatin Capsules Soft Gelatin Capsules

I- Hard Gelatin Capsules Raw Materials 1- Gelatin 2- Colorants 3- Process aids 4- Preservative 5-Plasticizers

1- Gelatin Gelatin is a product obtained from the skin, white connective tissue and bones of animals. It is prepared by the hydrolysis of collagen, which is the main protein constituent of connective tissues. There are two main types of gelatin: Type A, which is produced by acid hydrolysis, Type B, which is produced by basic hydrolysis. It is found in commerce in the form of fine powder, a coarse powder, shreds, flakes, or sheets.

1- Gelatin Reasons for using gelatin it is non-toxic, widely used in foodstuff, and acceptable for use worldwide It is readily soluble in biological fluids at body temperature. It is a good film-forming material, producing a strong flexible film. Solutions of high concentration, 40% w/v are mobile at 50 °C. Other biological polymers, such as agar, are not. A solution in water or in a water-plasticizer blend undergoes a reversible change from above ambient temp.

2-Colorants The colorants that can be used are of two types: 1- Water-soluble dyes 2- water-insoluble pigments. To make a range of colors dyes and pigments are mixed together as solutions or suspension. Dyes can be subdivided in the azo dyes- (have a N=N- linkage) and non-azo dyes. Most dyes used currently are of non-azo class and the three most widely used are: - erythrosine (E 127), - indigo carmine (E 132) - quinoline yellow (E104).

2-Colorants Two types of pigment are used : 1- iron oxides (E 172) 2- black, red and yellow and titanium dioxide ( E171), which is white and used to make the capsule opaque. In the last few years :- there has been a move away from soluble dyes to pigments, particularly the iron oxides, because they are not absorbed on ingestion.

3- Process aids The US NF describes the use of gelatin containing not more than 0.15% w/w of sodium lauryl sulfate for use in hard gelatin capsule manufacture. This function as a wetting agent, to ensure that the lubricated metal moulds are uniformly covered when dipped into the gelatin solution.

4-Preservatives Preservative were formerly added to hard capsules as an in-process aid in order to prevent microbiological contamination during manufacture. In the finished capsules the moisture levels, 13.0-16.0 % w/v are such that they will ------ not support bacterial growth because the moisture is too strongly bonded to the gelatin molecule.

Preparation of filled Hard Gelatin Capsules The preparation of filled hard gelatin capsules may be divided into the following steps: Development and preparing the formulation mixture and selecting the size capsule. 2. Filling the capsule shells 3. Cleaning and polishing

Eutectic mixtures of drugs, or mixtures require a diluent or absorbent such as magnesium carbonate, Kaolin, or light magnesium oxide to: separate physically the interacting agents and to absorb any liquefied material. Another method for separating drugs within a capsule is to place one of interfering substances in a small capsule that is then placed within a larger capsule containing the other formulative components. - For very small quantity of a potent drug pharmacists may insert a small tablet of the drug in each capsule

Limitation of capsule uses 1- Capsules of gelatin are unsuitable for the encapsulation of aqueous liquids, because water softens the gelatin to produce distortion of the capsules. Solved by :- absorbing a small amount of liquid by mixing it with an absorbent, inert powder. 2- some liquids such as fixed or volatile oils that do not interfere with the stability of the gelatin shells may be placed in gelatin capsules which then may be sealed to ensure the retention of liquid. In large scale production, liquids are placed in soft gelatin capsules which are sealed during their manufacture.

capsule size 1- Capsule size 8sizes ;000, 00, 0, 1, 2, 3, 4, 5 (which one is the largest). The size selected for use is deteremined by the ; amount of material to be encapsulated.

Soft Gelatin Capsules

Soft gelatin capsules (Softgels) Soft gelatin capsules (Softgels) consist of a liquid or semisolid matrix inside a one-piece outer gelatin shell. The drug compound itself may be either: in solution or in suspension. The fill matrix may be: - hydrophilic (for ex. Polyethylene glycols) - lipophilic (such as triglyceride vegetable oils, volatile and nonvolatile, aromatic, aliphatic hydrocarbon) or - mixture of both hydrophilic and lipophilic ingredients. Softgel fill matrices may be: microemulsions or nanoemulsions encapsulated as preconcentrates in softgel.

Characters of soft gelatin capsules Shape: oblong, oval, or spherical Shell consists of: gelatin, water and a plasticizer. may be transparent, or opaque, can be colored and flavored. Preservative are not required owing to the low water activity in the finished product. Softgel can be coated with enteric-resistant or delayed –release material.

Types of Softgels Orally administrated softgels: containing solutions or suspensions that release their contents in the stomach Chewable softgels, where a highly flavored shell is chewed to release the drug liquid fill matrix. The drugs may be present in both the shell and the fill matrix. Suckable softgels consist of a gelatin shell containing the flavored medicaments to be sucked. Twist-off softgels are designed with a tag to be twisted thereby allowing access to the fill material. This type of softgel can be very useful for unit dosing of topical medication, inhalations, or indeed for oral dosing of a pediatric product. Meltable softgel, designed for use as "patient-friendly" pessaries or suppositories.

Rational for the selection of softgels as a dosage form. Improved drug absorption : Patient compliance and consumer preference Safety for potent and cytotoxic drugs Suitable for oils and low melting point drugs Dose uniformity of low-dose drugs. Product stability Manufacture of Softgels Gel mass : provides the softgel shell. Fill matrix for the contents. Rotary die encapsulation

Gel mass: provides the softgel shell. Gelatin shell is made up of gelatin, water, plasticizer and other materials (colorants, opacifiers, flavors). Plasticizers are used to make the softgel shell elasticity. They usually account 20-30% of the wet gel formulation. Glycerol, sorbitol Propylene glycol. Water, is an essential component of the softgel shell. Accounts for 30-40% of the wet gel formulation and its presence is important to ensure proper processing during gel preparation and soft encapsulation.

Finished product testing These normally include: Capsule appearance Active ingredient assay Related substances assay Fill weight Content uniformity Microbiological testing

Packaging and storing capsules Capsules are usually packed in glass or in plastic containers, (use a desiccant to prevent the absorption of excessive moisture by the capsules). Soft capsules have a greater tendency than do hard capsules to soften and adhere to one another, and they must be maintained in a cool, dry place. All capsules remain stable longer if maintained tightly sealed in a cool place of low humidity. The unit dose and strip packaging of solid dosage forms, particularly by the pharmacies which service nursing homes and hospitals, provides sanitary handling of the medications, ease of identification, and security in accountability for medications.

a- Capsule formulation In dry formulations, 1- active and inactive components must be blended thoroughly to assure a uniform powder mix for the capsule fill To achieve uniform drug distribution through-out a powder mix, it is advantageous if the density and particle size of the drug and non-drug components are similar. Particle size may be reduced by milling which results in particles ranging from about 50 to 1000 micrometers (µm) Depending upon the materials and equipment used, micronization produces particles in range 10 to 20 µm

Surfactants or wetting agents, as sodium lauryl sulfate in capsule and tablet formulations to facilitate the wetting of the drug substance by the bathing of gastrointestinal fluids to increase the dissolution of the drug and its absorption is a widely followed procedure in industry. Powders of poorly drugs have a tendency to float on the surface of the fluid and agglomerate to further minimize air-liquid contact and if wetting does not occur readily, dissolution is delayed. formulation can influence the bioavailability of a drug substance and can account for differences in drug effects which may be encountered between two capsule products of the same medicinal substance

b- Selection of capsule size The selection of capsule size is best done during the development of formulation. Smaller capsules may be required in cases in which the drug is to be taken by youngsters or by elderly patients, and more than a single capsule may be required to provide the dose of the drug. The cap is not used to hold powder but to retain it, and a capsule size should be selected to meet this requirement.

2- Filling of capsule Shells When filling small number of capsules in pharmacy, the pharmacist generally uses the " Punch method ". Some pharmacist wears surgical gloves or rubber finger to avoid handling the capsules with bare fingers. Because the amount of powder packed into a capsule depends upon the degree of compression, the pharmacist should punch each capsule in the same manner and after capping weigh it to ensure equal and accurate filling. each capsule should be weighed after filling to ensure accuracy. Such weighing protect against the uneven filling of capsules . - Granular material that dose not lend itself well to the punch Filling capsules: drug poured into each capsule individually from the powder paper on which it was first weighed.

a- Capsule formulation Adding: 1-glident: silicone dioxide 2-diluent (if needed): lactose, starch, cellulose 3-Lubricant: Mg stearate Notes: 1-In addition to providing bulk, diluents also provide cohesion to the powders, which is beneficial in the transfer of measured portions of the powder blend into capsule shells 2-If the amount of drug representing a usual dose is too large to place in a single capsule, two, or more capsules may be required to provide the desired dose of that particular drug.

3- Capsule Sealing In this process, two capsule parts are sealed with gelatin or polymer band at the seam of cap and body. More recently, a tamper- resistant seal on hard gelatin capsules was developed in which the contact areas of the cap and body are wetted with a mixture of water and ethanol and then thermally bonded at 104° to 113° F. Any attempts at the separation of a sealed capsule will result in the capsule's destruction, making tampering evident.