Capsules Fall 2024 PDF

Emmanuel O. Akala, R.Ph., Ph.D. Professor Department of Pharmaceutical Sciences College of Pharmacy Howard University...

Emmanuel O. Akala, R.Ph., Ph.D. Professor Department of Pharmaceutical Sciences College of Pharmacy Howard University Capsules: Objectives 1. Describe various types of capsules and the advantages and disadvantages of capsules as a dosage form. 2. Discuss hard gelatin capsules with emphasis on the composition and manufacture of hard gelatin capsule shells. 3. Discuss the preparation of filled hard gelatin capsules (Hand fill (punch method): Extemporaneous Filling of Hard Gelatin Capsules) 4. Describe the general considerations in the design of hard gelatin capsule powder formulations and choice of excipients 5. Discuss soft gelatin capsules with emphasis on the composition of the shell, advantages, disadvantages, formulation of soft gelatin capsules, and manufacture of soft gelatin capsules 6. Discuss the sealing techniques for tampering control in hard gelatin capsule 7. Understand the newest Hypromellose (Hydroxypropyl methylcellulose (HPMC) VCAPS Plus) capsule shells.  CAPSULES (Emmanuel O. Akala, R. Ph., Ph.D.) Capsules are solid dosage forms in which medicinal agents and/or inert substances are enclosed within a small shell of gelatin. Gelatin capsule shells may be hard or soft depending on their composition. The vast majority of filled capsules are intended to be swallowed whole by the patient for the benefit of the medication contained therein. However, it is not unusual practice in hospitals and extended care facilities for a caregiver to open capsules or crush tablets to mix with food or drink, especially for children or other patients unable to swallow solid dosage forms. This should be done only with the concurrence of the pharmacist since the drug release characteristics of certain dosage forms could be altered and adversely affect the patient’s welfare. Advantages of capsules as a dosage form: Elegance; ease of administration (easily swallowed); portability; tasteless shell; taste masking; small number of excipients in the formulation; little pressure in the manufacture; imprints (company or product identification information); versatility (can be developed for liquid (soft gelatin capsules) and solids (hard gelatin capsules); easily filled either extemporaneously or in large quantity commercially; hard gelatin capsules are uniquely suitable for blinded clinical trials. Disadavantages: Highly soluble salts (e.g., iodides, bromides, or chlorides) generally should not be dispensed in hard gelatin capsules. Their rapid release may cause gastric irritation owing to the formation of a high drug concentration in localized areas. A somewhat related concern is that both hard gelatin capsules and tablets may become lodged in the esophagus, where the resulting localized high concentration of certain drugs (doxycycline, potassium chloride, indomethacin, and others) may cause damage. Hard Gelatin Capsules Hard gelatin capsule shells are used to manufacture most of the commercially available medicated capsules. They are also commonly employed in clinical drug trials, to compare the effects of an investigational drug to another drug product or placebo. Hard gelatin capsules also are used by the community pharmacist in the extemporaneous compounding of prescriptions. The empty capsule shells are made from a mixture of gelatin, sugar and water (the water content is between 13 to 16 %). As such, they are clear, colorless, and essentially tasteless. They may be colored with various FD&C and D&C dyes. They may be made opaque by adding agents such as titanium dioxide. Most commercially available medicated capsules contain combinations of colorants and opaquants or opacifyng agents to make them distinctive, many with caps and bodies of different colors. Preservatives are also added Composition of gelatin Gelatin is obtained by the partial hydrolysis of collagen obtained from the skin, white connective tissue, and bones of animals. In commerce, it is available in the form of a fine powder, a coarse powder, shreds, flakes, or sheets There are two types of gelatin depending on the manner of extraction: Type A gelatin is obtained from the acid hydrolysis, mainly from pork skin. pI (isoelectric point) is 7.0-9.0 Type B is obtained from alkali hydrolysis of animal bones. pI (isoelectric point) is 4.8-5.0) Either of them can be used but both are used to impart optimization (Bone gelatin offers firmness ; while skin gelatin contributes claritiy and plasticity). The Manufacture of Hard Gelatin Capsule Shells Hard gelatin capsule shells are manufactured in two sections, the capsule body and a shorter cap. The two parts overlap when joined, with the cap fitting snugly over the open end of the capsule body. The shells are produced industrially by the mechanical dipping of pins or pegs of the desired shape and diameter into a temperature-controlled reservoir of melted gelatin mixture as discussed below. (A) Dipping solution: Hot, demineralized water is used in the preparation of the dipping solution. Initially, a 30-40% w/w solution of gelatin is prepared in large stainless steel tanks. Vacuum may be applied to assist in the removal of entrapped air from this viscous preparation. Portions of this stock solution are removed and mixed with any other ingredients, as required, to prepare the dipping solution. At this point, the viscosity of the dipping solution is measured and adjusted. The viscosity of this solution is critical to the control of the thickness of the capsule walls. (B) Dipping : Pairs of stainless steel pins are dipped into the dipping solution to simultaneously form the caps and bodies. The pins are lubricated with a proprietary mold- release agent. The pins are at ambient temperature (about 22 oC); whereas the dipping solution is maintained at a temperature of about 500C in a heated, jacketed dipping pan. The length of time to cast the film has been reported to be about 12 sec, with larger capsules requiring longer dipping times. (C) Rotation: After dipping, the pins, withdrawn from the dipping solution, are elevated and rotated 2-1/2 times. This rotation helps to distribute the gelatin over the pins uniformly and to avoid the formation of a bead at the capsule ends. After rotation, the film is set by a blast of cool air. (D) Drying: The racks of gelatin-coated pins then pass into a series of four drying ovens. Drying is done mainly by dehumidification by passing large volumes of dry air over the pins. A temperature elevation of only a few degrees is permissible to prevent film melting. Drying must not be too rapid to prevent “case hardening.” Overdrying must be avoided, as this could cause films to split on the pins from shrinkage or at least make them too brittle for the later trimming operation. Underdrying will leave the films too pliable or sticky for subsequent operations. (E) Stripping: A series of bronze jaws (softer than stainless steel) strip the cap and body portions of the capsules from the pins. (F) Trimming : The stripped cap and body portions are delivered to collets in which they are 2  firmly held. As the collets rotate, knives are brought against the shells to trim them to the required length. (G) Joining : The cap and body portions are aligned concentrically in channels and the two portions are slowly pushed together. The entire cycle takes about 45 mins; however, about two-thirds of this time is required for the drying step alone. 3 Preparation of Filled Hard Gelatin Capsules Hand fill (punch method): Extemporaneous Filling of Hard Gelatin Capsules A. General Considerations: 1). The active and inactive ingredients must be blended together thoroughly to assure a uniform powder mix for filling into the capsule. Occasionally, the particle size is reduced (usually by trituration) to have a fine and uniform powder, as uniform distribution of drug and nondrug components are achieved if the density and particle size are similar. Granular powders do not pack readily in capsules and crystalline materials, especially those which consist of a mass of filament – like crystals such as quinine salts, are not fitted easily into capsules unless powdered. 2). Eutectic mixtures that tend to liquefy may be dispensed in capsules if a suitable absorbent such as magnesium carbonate is used. 3). Potent drugs given in small doses usually are mixed with an inert diluent such as lactose, microcrystalline cellulose, and pregelatinized starch, before filling into capsules. 4). When incompatible materials are prescribed together, it is sometimes possible to place one in a smaller capsule and then enclose it with the second drug in a larger capsule. B. Selection of Capsules: 1). Hard gelatin capsules are used to encapsulate between about 65 mg and 1 g of powdered materials, including drug and any diluent required. The amount of drug to be present in a single capsule is first determined, and the amount of diluent, if any, is determined subsequently on the basis of its being needed to add bulk to the formulation or to separate chemically incompatible components of the formulation. 2). It is usually necessary for the pharmacist to determine the size of the capsule needed for a given prescription through experimentation. The experienced pharmacist, having calculated the weight of material to be held by a single capsule, often will select the correct size immediately. 3). Fortunately there are pieces of information in the literature to guide in the selection of the right type of capsule as discussed below: (a). For human use, empty gelatin capsules are manufactured in eight sizes, ranging from 000 (the largest) to 5 (the smallest). The volumes, densities and approximate capacities for the traditional eight sizes are shown in the three tables 4  below. The largest size normally acceptable to patients is a No. 0. Size 0 hard gelatin capsule having elongated body (size 0el) also is available that provides greater fill capacity without an increase in diameter. (b). Three larger sizes are available for veterinary use: 10, 11, and 12 having capacities of about 30, 15, and 7.5 g respectively. C. Filling the Capsule: 1). Usually the powder is placed on paper and flattened with a spatula so that the layer of powder is not greater than about 1/3 the length of the capsule which is being filled. This helps to keep the hands and the capsules clean. Some pharmacists wear surgical gloves or rubber finger cots to avoid handling capsules with bare fingers. 2). The cap is removed from the selected capsule and held in the left hand; the body is held between the thumb and forefinger and pressed repeatedly into the powder until it is filled. The cap is replaced and the capsule is weighed. The spatula is helpful in pushing the last quantity of material in to the capsule. 3). In prescription filling, it is wise to check the weight of each filled capsule. 4). There are a number of hand-operated capsule machines (about 2000 per day) which many community pharmacists find useful. D. Cleaning and Polishing the Capsules. 5 Capsules prepared on a small scale or on a large scale may have small amounts of the powder formulation adhering to the outside of the capsules. This powder, which may be bitter or otherwise unpalatable, should be removed before packaging or dispensing to improve the appearance of the capsules and to preserve their quality of being tasteless on administration. On a small scale, capsules may be cleaned individually or in small numbers by rubbing them with a clean gauze or cloth. On a large scale, many capsule-filling machines are affixed with a cleaning vacuum that removes any extraneous material from the capsules as they exit the equipment. 6  General Considerations in the Design of Hard Gelatin Capsule Powder Formulations and Choice of Excipients I. Active Ingredient The amount and type of active ingredient influences capsule size and the nature and amount of 7 excipients to be used in the formulation. Although there are a growing number of exceptions, drugs having doses less than 10 mg are seldom formulated into capsules. These can be easily formulated into tablets that are more economical. Thus, the active ingredient often tends to make up a high percentage of the contents of a capsule. For drugs of low water solubility, the absorption rate may be governed by the dissolution rate. In such circumstances, if dissolution occurs too slowly, absorption efficiency may suffer. Drug stability in gastrointestinal fluids is another concern for slowly dissolving drugs, which can affect their bioavailability. Drugs of low water solubility are usually micronized to increase the dissolution rate. II Fillers Fillers (diluents) are often needed to increase the bulk of the formulation. The most common capsule diluents are starch, lactose, and dicalcium phosphate. Modifications of these materials for direct-compression tableting, such as pregelatinized starch (Starch 1500, Colorcon Inc., West Point, PA) or spray-processed lactose (Fast-Flo, lactose, Foremost, Div. Wisconsin Dairies, Baraboo, WI) or unmilled dicalcium phosphate dihydrate (Ditab, Rhone-Poulenc Basic Chemicals Co., Shçlton, CT; Emcompress, Mendell, A Penwest Co., Patterson, NY) can also be used. These substances improve flow and compactibility while maintaining the basic properties of the original materials. III Glidants Glidants are used to improve the fluidity or flowability of powders. They are fine particles that appear to coat the particles of the bulk powder and enhance fluidity by one or more of several possible mechanisms: (a) reducing roughness by filling surface irregularities, (b) reducing attractive forces by physically separating the host particles, (c) modifying electrostatic charges, (d) acting as moisture scavengers, and (e) serving as ball bearings between host particles. Usually, there is an optimum concentration for flow, generally less than 1% and typically 0.25—0.50%. The optimum concentration may be related to the concentration just needed to coat the host particle. Exceeding this concentration usually will result in either no further improvement in flow and, even, a worsening of flow. Glidants include the colloidal silicas, corn starch, talc, and magnesium stearate. IV Disintegrant Although tablet disintegrants are being used in some capsule formulations, until recently, the role they play in capsules has been a relatively unexplored area. With the advent, in recent years, of filling machines that actually compress capsule contents, together with the development of newer disintegrants that have superior swelling or moisture-absorbing properties, disintegrants appear to warrant serious consideration in modern capsule formulations. These newer disintegrants, which have been called “super disintegrants”, include croscarmellose sodium, type A (AcDiSol, FMC Corp., Food and Pharmaceutical Products, Philadelphia, PA), sodium starch glycolate (Primojel, Generichem Corp., Little Falls, NJ; Explotab, Mendell, A Penwest Co., Patterson, NY), and crospovidone (Polyplasdone XL, ISP Corp., Wayne, NJ). V Surfactants Surfactants may be included in capsule formulations to increase the wetting of the powder mass and enhance drug dissolution. The “waterproofing” effect of hydrophobic lubricants (glidants) may 8 be offset by the use of surfactants. Numerous studies have reported the beneficial effects of surfactants on disintegration and deaggregation or drug dissolution VI Hydrophilization Another approach to improving the wettability of poorly soluble drugs is to treat the drug with a solution of a hydrophilic polymer. It has been reported that both wettability of the powder and the rate of dissolution of hexobarbital from hard gelatin capsules could be greatly enhanced if the drug was treated with methylcellulose or hydroxyethylcellulose. SOFT GELATIN CAPSULES Advantages Several advantages of soft gelatin capsules derive from the fact that the encapsulation process requires that the drug be a liquid or at least dissolved, solubilized, or suspended in a liquid vehicle. Moreover, a higher degree of homogeneity is possible in liquid systems than can be achieved in powder blends. A content uniformity of ± 3% has been reported for soft gelatin capsules manufactured in a rotary die process. Another advantage that derives from the liquid nature of the fill is rapid release of the contents with potential enhanced bioavailability. The proper choice of vehicle may promote rapid dispersion of capsule contents and drug dissolution. Soft gelatin capsules are hermetically sealed as a natural consequence of the manufacturing process. Thus, this dosage form is uniquely suited for liquids and volatile drugs. Many drugs subject to atmospheric oxidation may also be formulated satisfactorily in this dosage form. It has been shown that the soft gelatin shell can be an effective barrier to oxygen. Disadvantages One disadvantage of soft gelatin capsules is that such products must be contracted out to a limited number of firms having the necessary filling equipment and expertise. Materials must be shipped to the soft gelatin capsule facility and products must be shipped back to the pharmaceutical manufacturer for final packaging and distribution. Additional quality control measures may be required. Soft gelatin capsules are not an inexpensive dosage form, particularly when compared with direct compression tablets There is a more intimate contact between the shell and its liquid contents than exists with dry-filled hard gelatin capsules, which increases the possibility of interactions. For instance, chloral hydrate formulated with an oily vehicle exerts a proteolytic effect on the gelatin shell; however, the effect is greatly reduced when the oily vehicle is replaced with polyethylene glycol. Drugs can migrate from an oily vehicle into the shell, and this has been related to their water solubility and partition coefficient between water and the nonpolar solvent. Composition of the Shell of Soft Gelatin Capsule 9 Similar to hard gelatin shells, the basic component of soft gelatin shells is gelatin; however, the shell has been plasticized by the addition of glycerin, sorbitol, or propylene glycol. Other components may include dyes, opacifiers, preservatives, and flavors. The ratio of dry plasticizer to dry gelatin determines the “hardness” of the shell and can vary from 0.3-1.0 for a very hard shell to 1.0—1.8 for a very soft shell. Up to 5% sugar may be included to give a “chewable” quality to the shell. The basic gelatin formulation from which the plasticized films are cast most usually consists of 1 part gelatin, 1 part water, and 0.4—0.6 part plasticizer. The residual shell moisture content of finished capsules will be in the range of 6—10%. Formulation of Soft Gelatin Capsules The formulation for soft gelatin capsules involves liquid, rather than powder technology. Materials are generally formulated to produce the smallest possible capsule consistent with maximum stability, therapeutic effectiveness, and manufacture efficiency. Soft gelatin capsules contain a single liquid, a combination of miscible liquids, a solution of a drug in a liquid, or a suspension of a drug in a liquid. The types of vehicles used in soft gelatin capsules fall into two main groups. 1. Water-immiscible, volatile, or more likely nonvolatile liquids, such as vegetable oils, aromatic and aliphatic hydrocarbons (mineral oil), medium-chain triglycerides, and acetylated glycerides. 2. Water-miscible, nonvolatile liquids, such as low molecular weight polyethylene glycol (PEG- 400 and 600) have come into use more recently because of their ability to mix with water readily and accelerate dissolution of dissolved or suspended drugs. All liquids used for filling must flow by gravity at a temperature of 350C or less. Manufacture of Soft Gelatin Capsules Plate Process The oldest commercial batch process has been supplanted by more modern continuous processes. Equipment for the plate process may no longer be available. In general, the process involved (a) placing the upper half of a plasticized gelatin sheet over a die plate containing numerous die pockets, (b) application of vacuum to draw the sheet into the die pockets, (c) filling the pockets with liquor or paste, (d) folding the lower half of the gelatin sheet back over the filled pockets, and (e) inserting the “sandwich” under a die press where the capsules are formed and cut out. Rotary Die Process The first continuous process is the rotary die process that was invented in 1933 by R. P. Scherer. Aside from its being a continuous process, the rotary die process reduced manufacturing losses to a negligible level and content variation to ±1-3% range, both major problems with earlier processes. In this process, the die cavities are machined into the outer surfaces of two rollers (i.e., die rolls). The die pockets on the left-hand roller form the left side of the capsule; the die pockets on the right-hand roller form the right side of the die capsule. The die pockets on the two rollers match as the rollers rotate. Two plasticized gelatin ribbons (prepared in the machine) are continuously and simultaneously fed with the liquid or paste fill between the rollers of the rotary die mechanism. 10 Accogel Process A continuous process for the manufacture of soft gelatin capsules filled with powders or granules was developed by Lederle Laboratories in 1949. Sealing Techniques for Tampering Control In Hard Gelatin Capsule Some manufacturers make tamper-evident capsules by sealing the joint between the two capsule parts. One manufacturer makes distinctive-looking capsules by sealing them with a colored band of gelatin (KAPSEALS, Parke-Davis). If removed, the band cannot be restored without expert resealing with gelatin. Capsules may also be sealed through a heat welding process that fuses the capsule cap to the body through the double wall thickness at their juncture. The process results in a distinctive “ring” around the capsule where heat welded. Still another process utilizes a melting-point-lowering liquid wetting agent in the contact areas of the capsule’s cap and body and then thermally bonds the two parts using low temperatures (40-45 oC). Industrial capsule sealing machines are capable of producing 60,000 to 150,000 gelatin banded, heat welded, or thermally coupled capsules per hour Although difficult and tedious, extemporaneously prepared capsules may be sealed by lightly coating the inner surface of the cap with a warm gelatin solution immediately prior to 11 placement on the filled capsule body. 12 Vcaps® Plus Capsules | Capsugel https://www.capsugel.com/biopharmaceutical-products/vcaps-plus-capsules 1 of 5 4/9/2018, 10:57 AM Vcaps® Plus Capsules | Capsugel https://www.capsugel.com/biopharmaceutical-products/vcaps-plus-capsules 2 of 5 4/9/2018, 10:57 AM Vcaps® Plus Capsules | Capsugel https://www.capsugel.com/biopharmaceutical-products/vcaps-plus-capsules 3 of 5 4/9/2018, 10:57 AM Vcaps® Plus Capsules | Capsugel https://www.capsugel.com/biopharmaceutical-products/vcaps-plus-capsules 4 of 5 4/9/2018, 10:57 AM Vcaps® Plus Capsules | Capsugel https://www.capsugel.com/biopharmaceutical-products/vcaps-plus-capsules 5 of 5 4/9/2018, 10:57 AM