Lipid-based drug delivery systems have been intensively investigated as a means of delivering poorly water-soluble drugs. Upon ingestion, the lipases in the gastrointestinal tract digest lipid ingredients, mainly triglycerides, within the formulation into monoglycerides and fatty acids. While numerous studies have addressed the solubility of drugs in triglycerides, comparatively few publications have addressed the solubility of drugs in fatty acids, which are the end product of digestion and responsible for the solubility of drug within mixed micelles. The objective of this investigation was to explore the solubility of a poorly water-soluble drug in fatty acids and raise the awareness of the importance of drug solubility in fatty acids. The model API (active pharmaceutical ingredient), a weak acid, is considered a BCS II compound with an aqueous solubility of 0.02 μg/mL and predicted partition coefficient >7. The solubility of API ranged from 120 mg/mL to over 1 g/mL in fatty acids with chain lengths across the range C18 to C6. Hydrogen bonding was found to be the main driver of the solubilization of API in fatty acids. The solubility of API was significantly reduced by water uptake in caprylic acid but not in oleic acid. This report demonstrates that solubility data generated in fatty acids can provide an indication of the solubility of the drug after lipid digestion. This report also highlights the importance of measuring the solubility of drugs in fatty acids in the course of lipid formulation development.

The kinetics of water transport into tablets, and how it can be controlled by the formulation as well as the tablet microstructure, are of central importance in order to design and control the dissolution and drug release process, especially for immediate release tablets. This research employed terahertz pulsed imaging to measure the process of water penetrating through tablets using a flow cell. Tablets were prepared over a range of porosity between 10% to 20%. The formulations consist of two drugs (MK-8408: ruzasvir as a spray dried intermediate, and MK-3682: uprifosbuvir as a crystalline drug substance) and NaCl (0% to 20%) at varying levels of concentrations as well as other excipients. A power-law model is found to fit the liquid penetration exceptionally well (average R2>0.995). For each formulation, the rate of water penetration, extent of swelling and the USP dissolution rate were compared. A factorial analysis then revealed that the tablet porosity was the dominating factor for both liquid penetration and dissolution. NaCl more significantly influenced liquid penetration due to osmotic driving force as well as gelling suppression, but there appears to be little difference when NaCl loading in the formulation increases from 5% to 10%. The level of spray dried intermediate was observed to further limit the release of API in dissolution.

N,N,N',N'-Tetramethylimidazolidinium dichloride (1-Im-1 2Cl) has been studied as a model system for cation-anion interactions in the interfacial regions of gemini micelles by X-ray crystallography, density functional theory (DFT) calculations, and infrared spectroscopy. Single crystals of 1-Im-1 2Cl contain 1-Im-1 dications, whose five-membered rings adopt a distorted envelope conformation. Eight chloride anions surround each dication, two of which are cradled above and below the five-membered ring (apical) and six of which are dispersed about the periphery of the ring (equatorial). The cations and anions are linked in the solid state by an extensive network of weak C-H...Cl hydrogen bonds that involve all of the H atoms of the dication. The calculated (DFT at the 6-31+G(d) level) structure of the asymmetric unit, which consists of a dication and two apical chloride ions, closely resembles the equivalent unit in the crystal structure with respect to bond distances and angles, the conformation of the 1-Im-1 ring, and the nature and location of the C-H...Cl hydrogen bonds. The calculated IR spectrum predicts a number of absorptions in the 3000 cm(-1) region, assigned as C-H...Cl stretching modes, which are consistent with the presence of an intense band in the observed IR spectrum of the crystals. Over all, this study supports the notion that apical chloride ions interact more strongly with gemini surfactant headgroups by forming multiple hydrogen bonds in ion pairs of a type that cannot be present in the corresponding ion pairs of quaternary headgroups with counterions of single-chain surfactants.

Purpose Lean stability is a science- and risk-based initiative which utilizes the enhanced understanding of drug substance and drug product physical and chemical characteristics to (1) reduce and optimize the design of standard stability protocols; (2) expedite the generation of stability data without impact to safety, efficacy, or quality of the product; and (3) decrease time to market for innovative drugs. Lean stability was introduced in the early 2000s [ICH: Guideline Q1A(R2) (2003), ICH: Guideline Q1D (2002)] followed by reduced stability protocols, focusing on the critical quality attributes and critical time points, being reported in the literature [Skrdla et al. (J Pharm Biomed Anal 50: 794–796, 2009)]. While the concept of lean testing is not entirely new, and it is currently a part of several regulatory guidances, it continues to evolve and gain acceptance of the industry and regulators. Methods In this review, twelve case studies are presented where stability data was collected during clinical, registration, and post-approval phases of the product development. Results Case studies summarize the lean stability testing design, the strategies applied during the regulatory filing and the outcomes of the regulatory filings. Conclusion The authors expect that the case studies presented in this review will increase the visibility of lean stability, facilitate overcoming of the existing challenges, and accelerate the global regulatory acceptance of lean stability practices in the industry.

Purpose This paper summarizes results from a recent pharmaceutical industry survey to understand the adoption status of science- and risk-based approaches in pharmaceutical stability (lean stability) in regulatory submissions across the full pharmaceutical product life cycle and to ascertain whether companies are deriving their stability strategies based on scientific risk or applying generic strategies. Methods A comprehensive survey was distributed to pharmaceutical companies affiliated with the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) to solicit non-proprietary responses pertaining to regulatory strategies for stability monitoring across the product life cycle, perceived risks, and health authority feedback. Results Among the 19 responding companies, utilization of lean stability approaches varied with respect to (1) phase of product life cycle, (2) specific product quality attributes cited in effective ICH guidances or which demonstrated shelf-life limiting stability trends, and (3) the degree of perceived risk of rejection by health authorities based upon companies’ degree of experience from previous regulatory submissions. Conclusion Continued collaboration between the pharmaceutical industry and health authorities—through case studies and revision/harmonization of regulatory guidances—will be essential for continued implementation of lean stability strategies to accelerate delivery of innovative medicines to the clinic and to the market.