Issue link: https://www.e-digitaleditions.com/i/1022930
34 September 2018 Tablets & Capsules Liquid or low-melting-point APIs Processing liquid or low-melting-point APIs and SEDDS into an SODF other than an LFHC is difficult. Processing such APIs for use in tablets or powder-filled capsules requires large excipient amounts and multiple processing steps but is often much simpler for LFHCs. For example, combining ibuprofen, which has a melting point of 75°C, with PEG 6000 at 70°C forms a flowable mass that can easily be filled into hard capsules. Highly potent APIs Highly potent APIs (HPAPIs) pose three major prob- lems for formulators. First, it can be difficult to achieve content uniformity because the HPAPI is present in smaller quantities than with a typical API. Second, you must protect workers from exposure to the dust gener- ated when processing HPAPI formulations such as anti-cancer treatments, immunosuppressants, steroids, hormonal treatments, and anti-diabetics. Third, potential residue left on the equipment after processing HPAPIs makes the cleaning process tedious. Using LFHCs can help avoid these problems. Because the API in a LFHC is uniformly distributed in liquid, variations caused by bulk density, particle size, or flow properties are eliminated. The mixture is filled by volume using accurate, ser- vo-based dosing pumps. As a result, content uniformity is generally much better in LFHCs than in powder-filled capsules or tablets. Poorly soluble APIs Many new APIs have poor aqueous solubility (BCS Class II and IV) or permeability (BCS Class III). Adding a solubilizer or emulsifier or processing the API as a SEDDS can enhance bioavailability. Formulating a poorly soluble API as a lipid system may increase permea- bility because inducing lymphatic absorption can bypass hepatic degradation. The FDA approved Absorica, a LFHC made by Ranbaxy/Sun Pharma, via a 505(b)(2) application because the API (isotretinoin) absorbed better in fasting patients than it did in the original Roaccutane/Accutane softgel capsules from Roche. Formulators can use lipid excipients to target lymphatic transport or circumvent the impact of transporters and metabolizing enzymes in the gastrointes- tinal (GI) tract. Also, milling an API in a liquid medium avoids agglomeration of nanoparticles, and the API can then be filled into LFHCs as a suspension. For example, itraconazole nanocrystals prepared according to a process patented by MW Encap in 2016 initiate dissolution much faster than unmilled itraconazole [2]. Sustained-release APIs LFHCs also make it possible to formulate a sus- tained-release drug product while easily keeping part of the API as an immediate-release portion. Companies have prepared such products by using excipients that influence the hydrophilic-lipophilic balance of the semi- sulation technology can eliminate many problems associ- ated with softgel capsules, including high manufacturing cost, gelatin waste, cross-contamination, migration of the API into the capsule shell, and bioavailability problems [1]. In this article, I will discuss how LFHCs can help to overcome common formulation problems and provide examples of successfully marketed LFHC products. Combination products LFHCs can contain tablets or microtablets, pellets, smaller capsules, or a combination of these in addition to the liquid fill, as shown in Photo 1. This allows formula- tors to develop products with multiple APIs without caus- ing compatibility problems or to easily manage different release patterns for a single or multiple APIs. For exam- ple, the GlaxoSmithKline LFHC product approved in 2010 and marketed as Jalyn in the US and Combodart in Europe contains 0.4-milligram tamsulosin hydrochloride modified-release pellets and a 0.5-milligram dutasteride softgel capsule. The ability to combine multiple fill materials can be beneficial in the nutritional supplement industry as well. For example, a product might consist of an outer hard capsule that contains both plant oils and a smaller enter- ic-coated HPMC capsule filled with probiotic bacteria. The coated inner capsule would create an effective mois- ture barrier for the probiotic bacteria in the stomach, allowing these otherwise incompatible ingredients to be administered together in a single dosage form. Hygroscopic APIs Processing hygroscopic APIs and keeping them dry and stable during the shelf life of a product can be diffi- cult. Incorporating such APIs into a molten excipient such as PEG, poloxamer, or wax at temperatures up to 70°C and filling the hard capsules while the material is hot can help solve this problem. The excipient solidifies at ambi- ent temperature, providing a stable matrix that protects the API from moisture. For example, vancomycin hydro- chloride was initially formulated as lyophilized powder in ampoules for injection. Mixing the API into molten PEG 6000 and filling it into hard gelatin capsules protected the hygroscopic API from moisture and allowed it to be suc- cessfully marketed as a solid oral dosage form (SODF). Photo 1: LFHCs allow formulators to develop combination products with multiple APIs or API release patterns. Courtesy of ACG