Drug products, formulation development surfactants

As discussed in Sect. 18.3, several models are available and can be applied with limited amounts of experimental data in combination with calculated molecular descriptors. These models are extremely valuable at the early stage of development of the API. A quick decision can be made regarding if ASD is an applicable approach for the candidate. Once this question is answered, the selection of an appropriate polymer comes in as the next step. If other additives are needed, for example, a surfactant to improve the manufacturability or to enhance the pharmacokinetic (PK) performance, the implication on system stability has to be assessed. The different formulations developed can be rank ordered based on their stability under severe temperature and humidity conditions. When the composition of the ASD is finalized, a more systematic stress test is used to understand the recrystallization risk. Though the changes in physicochemical properties by and large appear in a nonlinear fashion, the stress tests normally are sufficient to assess the risks, thus providing the formulation scientists confidence to estimate the stability of the drug product. 

Solution stability is a very important parameter to assess during development and for this discussion will be defined as the ability of the co-crystal components to stay in solution and not readily crystallize or precipitate. A variety of media can be introduced, including water, simulated gastric fluid (SGF), simulated intestinal fluid (SIF), formulation vehicles, and buffered solutions. In many instances, these experiments can be coupled with solubility or dissolution experiments to obtain a more complete picture of the behavior and the solid form remaining at the end of the experiment. Because dissociation of a cocrystal often occurs and precipitation of a less soluble form (either one of the components or another co-crystal) can result, solution stability studies should be considered early in development of a potential drug product. Attention has been focused on formulation approaches to stabilize the co-crystal (or cocrystal components) in solution by addition of surfactants to avoid the problem of recrystallization. One of the first reports on this approach was published by Remenar et al. on a celecoxibmicotinamide co-crystal in various formulation vehicles (110% sodium dodecylsulfate (SDS) and polyvinylpyrrolidone (PVP)) in order to understand the solid form that may result upon contact with... 

Formulation studies are performed to develop a suitable vehicle to solubilize the drug for administration to patients, generally by intravenous injection or infusion in the case of cancer. The low solubility of many natural products in water poses considerable problems, but these can be overcome by use of co-solvents or emulsifying agents (surfactants) such as Cremophore EL (polyoxyethylated castor oil). 

Sprays are liquid dosage forms aerosolized into the oral cavity for transmucosal drug delivery. Due to the formation of small droplets upon aerosolization of the liquid, sprays can achieve shorter lag times and a faster onset of action than other liquid formulations. Oral-lyn is a micellar system utilizing a blend of surfactants as permeation enhancers and formulation stabilizers. The product is one application of the RapidMist system patented by Generex Biotechnology Corporation that has also been used to develop products for vaccine delivery, pain management, and weight loss. 

Cationic surfactants. Cationic surfactants, frequently belonging to alkylpyridinum, alkyl-benzyldimethylammonium and trimethylammonium types, are conunonly determined in skin care cosmetics and hair and mouth formulations, using reversed-phase LC with UV, conductivity or RI detection. Thus, Benassi et al. (1989) developed a method to analyse cetylpyridinium chloride and alkylbenzyldimethyl chloride in cosmetic products (mouthwashes, dental products. ..) by reversed-phase LC. The necessary chromatographic conditions comprise a deactivated bonded-phase column and an acetonitrile/aqueous phosphate in acid pH solution as a mobile phase. LC analysis of multicomponent het-erophasic matrixes, such as cosmetic products, drugs and foods, has been studied by Bettero et al. (1990). Ci2 i6 alkylbenzyldimethylammonium homologues were separated using UV detection after dilution in a tetrahydrofuran water solution. 

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