[series of topics] soft capsule technology and production process (5)

At present, about 40% of new chemical entities (nces) in new drug development have poor biological characteristics, such as low water solubility and / or low permeability These unsatisfactory characteristics pose a great challenge to the oral absorption of compounds and the development of oral bioavailable formulations There is a growing interest in the development of soft capsule formulations of poorly water-soluble compounds (BCS II or IV) Compared with other oral dosage forms, soft capsule dosage forms have several advantages, such as: providing a liquid matrix for dissolving and improving the oral bioavailability of unit dose solid preparations, for delivering low-dose and ultra-low-dose compounds, providing delivery methods of low melting point compounds, and minimizing the possible dust in the production process, thus improving the producer Safety production conditions of personnel However, due to the dynamic characteristics of the soft capsule formulation, its stability within its shelf life is facing some challenges The purpose of this review is to provide a deep discussion on soft capsule preparation for pharmacists who are engaged in the development of soft capsule formulation Key words: soft capsule, formulation development, encapsulation, poor solubility, bioavailability, gelatin crosslinking, dissolution, physical stability, chemical stability Content formulation development In general, the solubility determination is to balance the suspension containing excessive compounds in a constant temperature (for example, 25 ℃, 37 ℃) solvent, and collect the supernatant after centrifugation filtration of the suspension, and then determine the dissolution by using appropriate analytical methods When developing the content of soft capsule in the form of solution, it is necessary to optimize the determination method and take into account the water transfer process in the soft capsule The solubility of a compound in a certain solvent is determined by dissolving the incremental compound in a fixed volume solvent One solution of each concentration is mixed with water to simulate the process of water migration and retention in the soft capsule It is considered that the equilibrium solubility of the compounds in the compatible medium of soft capsules is the high concentration of the compounds which do not precipitate when they reach equilibrium in the presence of water When evaluating the solubility of compounds in a semi-solid or solid medium at room temperature, the preparation of solutions of various concentrations of compounds is carried out at a temperature above the melting point of the medium The solution is then cured at room temperature Observe the presence of any crystal in the compound in the solid solution under the polarization microscope regularly Table 1 gives an example of virtual development of a soft capsule content in the form of a solution of a compound In this example, the solubility of a compound in a water free medium is evaluated in increments of 10 mg / g (e.g., a large solubility of 50 mg / g) Depending on the type of medium (i.e., PEG, mixed medium chain glycerides, MCT or LCT), the content solution is mixed with water (during capsule filling, drying and balancing) at two expected exposure levels These solutions were placed at room temperature (RT) and accelerated stability conditions (e.g., 4 ° C and - 20 ° C) for approximately one month A solution representing the amount of water in the primary drying stage (higher) in 24 hours and the amount of water in the equilibrium stage (lower) in one month will be further studied (e.g 20 mg / g in the example) if no crystallization is observed by visual inspection and microscope under all stable conditions However, two aspects worth mentioning are water migration and its effect on the physical stability of the dissolved compounds in soft capsules First, although the compounds dissolved in the medium for soft capsule filling may precipitate when exposed to the higher moisture content environment in the primary drying stage, the compounds may re dissolve in the medium when the excess water is removed in the secondary drying stage Therefore, it will be meaningful to fill the solution preparation into the empty soft capsule (called air filler) and monitor the precipitation re dissolution phenomenon during the cycle of high and low humidity Similar cycling procedures have been used by Raikes et al., although they are used to study the water absorbed by soft capsules under various relative humidity conditions Secondly, the water transfer from the capsule shell to the content may become advantageous when the content (some of the compounds are in the form of water-soluble salts) made by ess Technology (discussed in the chapter of solubility enhancers in hydrophilic media) is filled In the presence of added water and gelatin toner, it represents various possible capsule shell formulations for soft capsule filling, and evaluates the chemical stability of the selected content at 40 ℃ or higher In addition, the selected content prescription, without added water, can also be filled into the air filler and exposed to high temperature and humidity environment for chemical stability assessment It is important to consider that the gelatin toner and air filler selected for stability assessment contain various ingredients commonly used in the production of soft capsules, as it provides the flexibility of soft capsule products in multiple manufacturers (×) compound precipitation (crushing); (√) no precipitation, but it is eliminated due to the compound precipitation generated by the water level in the initial drying process within 24 hours; (√) the filling preparation with physical stability is further evaluated for chemical stability and subsequent filling A typical water content that originally existed in the medium; no water needed B may not be suitable for the filling preparation of MCT / LCT components, as it is not possible for water to migrate into these hydrophobic media When a compound is soluble and has definite stability in a soft capsule compatible medium, it can be potted into the soft capsule in the form of solution without too much prescription development work On the other hand, if the compound does not have sufficient solubility in a soft capsule compatible medium, it may need to be made into a suspension for filling The particle size of the dispersed material in the suspension shall be 180 μ m or less (passing 80 mesh screen) to achieve the acceptable mixing uniformity during the filling process of the soft capsule and the content uniformity of the end soft capsule product If the medium used to prepare the suspension has the ability to dissolve the compound, the dispersed material may undergo Oswald ripening and / or secondary nucleation, resulting in the change of particle size distribution and / or polymorph of the soft capsule product within the validity period In addition to the tests described above for the contents of the solution, the above tests on the stability of the suspension are generally achieved by conducting periodic influencing factor experiments between the preparation and the added water at 40 ℃ and 4 ℃ At the end of each cycle (for example, 48 hours at 40 ℃ and then 48 hours at 4 ℃ can be considered as a cycle), observe the change of particle size, morphology and polymorph of the sample Temperature cycling may accelerate the dissolution and recrystallization of the drug in the suspension at higher temperature, thus providing useful information for the physical stability of the soft capsule during its validity period However, the transformation may occur very quickly or slowly, or it may be reversible (mutualistic) or irreversible (univariant) Suspension contents may require suspension AIDS (thickening / tackifying) to prevent settling of the dispersed material and to maintain its uniformity during the soft capsule filling process Suspension AIDS widely used in oily preparations include beeswax, hydrogenated vegetable oil and glycerides with low HLB fatty acids (e.g gelucire ® 33 / 01, gelucire ® 39 / 01, gelucire ® 43 / 01, compritol ® 888, gattefossee) These suspensions, due to their hydrophobicity and high viscosity, can also greatly reduce the migration of water from the capsule shell to the content, and the diffusion of water-soluble components from the content to the capsule shell, so as to improve the physical stability of the capsule product Suspension aids for PEG based suspension formulations include high molecular weight pegs (e.g., PEG 1500, PEG 4000, PEG 6000), cellulosic polymers, colloidal silica, polyethylene pyrrolidone, calcium acetate, and monoglycerides, diglycerides, and triglycerides / monofatty acids and bisfatty acids mixtures of polyethylene glycol (e.g., gelucire ® 44 / 14, gelucire ® 50 / 13, gattefossee company) Polymorphism is a common phenomenon of many APIs and excipients The dissolution rate and bioavailability of various crystal forms of a compound are quite different These effects of polymorphs are particularly critical in the case of BCS class II and IV compounds The key is to start the development of the content formulation with a stable crystal form to prevent any possible precipitate of the dissolved compound due to the conversion of the unstable or metastable form to the stable form Ritonavir soft capsule product (Norvir ®, Abbott) is a classic example of soluble crystal form (I) changing into crystal form (II) with low solubility, thus affecting the quality of soft capsule product To be continued