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Hard gelatin packs for liquidsThursday, May 12, 2005 08:00 IST The new technology of packaging liquids in hard gelatin capsules is considered a major breakthrough. It can make a significant contribution to the development of efficacious pharmaceutical products by providing the flexibility to rapidly develop and test in-house formulations when only small quantities of drug substance is available. The process can be scaled-up and also kept in-house similar to the operations of tabletting or powder/pellet filling of hard gelatin capsules. The basic difference between the hard and soft gelatin encapsulation processes is that in the hard gelatin capsule process, the capsule is prefabricated and supplied empty, whereas in the soft gelatin capsule process the encapsulation and filling take place simultaneously. In-spite of the soft gel products being a conventional product, industry is having problem with the soft gel products both in manufacturing and in product by itself. Following are the few challenges that the manufacturers and the brand owners face: - Migration and degradation of moisture sensitive drugs, which are readily soluble in glycerol, can occur - Migration of a drug into the shell of a soft gelatin capsule, which may result in drug degradation - High permeability of the soft gel - The yellow spot on the soft gel capsule leading to poor aesthetics - Soft gelatin encapsulation process are contract manufacturers due to complex and messy operation - Large dimensional variation leading to problem in primary packaging - Low batch production is not possible due to huge and complex changeover required for each product - Poor aesthetics of the soft gel products Hard gelatin capsules: The right choice? - Due to the very nature of the process, the moisture content of the gelatin/plasticizer of the soft gelatin mass at this stage can be around 50%. The equilibrium moisture level only being reached after several days of storage, during which migration and degradation of moisture sensitive drugs, which are readily soluble in glycerol, can occur. - In contrast to hard gelatin capsule the soft gelatin capsule contains a plasticizer (usually glycerol at approx. 30% level) in addition to gelatin and water. The moisture uptake of soft gelatin capsules plasticized with glycerol is considerably higher than that for hard gelatin capsules. Another effect of the plasticizer is the migration of a drug into the shell of a soft gelatin capsule, which may result in drug degradation. - The oxygen transmission rate of a soft gelatin capsule film decreases with the level of glycerol in the film and with the moisture content. As the hard gelatin capsule wall contains no plasticizer the permeability of the hard gelatin capsule wall is lower than that of a soft gelatin capsule. As a result hard gelatin capsules containing even the highly odorous products like fish oil, valerian and garlic oil are odorless in contrast to the soft gelatin. - The yellow spot on the soft gel capsule is a cause of worry to most of the brand owners. This problem is completely eliminated when the liquid formulation is encapsulated in hard gelatin and band sealed. Moreover it adds to the aesthetics of the product with huge flexibility of colour and type of capsule to select. - The soft gelatin encapsulation process is in the hands of a few contract manufacturers. Due to the complexities of the process, rarely do pharmaceutical companies get involved in this operation. This means, that from an early stage of development, all activities must be contracted out. Many companies would prefer to keep these activities in-house for reasons of confidentiality, control over quality, control over the development process, availability of drug substance at the early stages of development and control over costs. This is possible by the liquid filling in hard gelatin and band sealing, which involves simple and clean in-house operation. - This technology can make a significant contribution to the development of efficacious pharmaceutical products by providing the flexibility to rapidly develop and test in-house formulations when only small quantities of drug substance are available. The process can be scaled-up and also kept in-house similar to the operations of tablet or powder/pellet filling of hard gelatin capsules. - In soft gelatin products the extent of variation in the dimension is more and this leads to the difficulty in blister packaging. This may lead to high rejection rate of the product during packaging. The hard gelatin capsules are prefabricated and have more stable and standard dimensions which is easy to blister packaging. - Soft gelatin plants are usually suited for large batch size but are not economical for small batch sizes. The change over from one product to other is not only critical but also records high switch over cost from one product to the other. Low batch size production can easily be handled in liquid filling in hard gelatin where switchover from one product to the next is easy and involves only minor changeover of parts and minimum cleaning. - The aesthetics of the soft gelatin leaves space for improvement. Also the choice of the colours are also limited due to the very nature of the process. In case of hard gelatin the colour choices are as per the requirement and the aesthetics are much better. The new dosage delivery system Conventionally hard gelatin capsule has been used as a solid dosage form products, formulated either as powder or pellets. However, market demands new and different ways of formulation delivery to be developed and launched in minimum time period. Liquids filled into hard gelatin capsules can fulfill some of these demands and in particular to drugs for which the liquid and semi-solid filled capsule is particularly relevant. - Poor bioavailability: The bioavailability of the poorly water-soluble drug dioxin could be significantly enhanced when formulated as a liquid in a hard gelatin capsule. This increases the effectiveness of the drug. - Low melting point : Materials which have low melting points or are liquid at room temperature present difficulties when formulating as dry powders, often requiring high concentrations of excipient to avoid processing problems. The manufacturing process can be considerably simplified (five step process to manufacture a tablet can be reduced to a simple mixing and filling operation) by filling as a hot melt into a hard gelatin capsule. Consumer acceptance was also enhanced due to the smaller size of the final dosage form. - Low dose / High potency: Drugs in this category present two main challenges; how to achieve acceptable content uniformity and how to control cross-contamination and worker protection. This type of drugs can be delivered easily in liquid dosage in hard gelatin capsule. - Content uniformity: The liquid filling operation is capable of achieving fill weight variations of < 1%. If a drug sub-stance is in solution or is uniformly dispersed in a liquid vehicle then it follows that good drug content uniformity can also be achieved (Triamterene at 25µg.) - Cross-contamination: Companies manufacturing solid dosage forms of hormones and cytotoxic agents from powders are forced to install extremely elaborate systems to reduce contamination. Incorporation of the highly potent agent into a liquid for filling into a hard gelatin capsule can reduce the dangers when working with such drugs. - Critical stability: Sensitivity to moisture is an aspect of formulation, which can be minimized by incorporating the drug into either a hydrophilic or lipophilic matrix. For example, the antibiotic vancomycin hydrochloride is highly hygroscopic and to achieve acceptable stability it needed to be formulated as a lyophilized powder for reconstitution. (Hard gelatin capsule filled with a PEG 6000 matrix). - Sustained release: By choosing an appropriate excipient the release rate of an active can be modified. For example Gelucire, which is available as a semi-solid with a range of melting points and HLB values, can be mixed to obtain different drug release rates compared the bioavailability of anoily semi-solid matrix of captopril in hard gelatin capsules with that of a tablet. - (Courtesy: Associated Capsules Pvt Ltd, Mumbai)
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