Critical Quality Attributes of Topical Semi-solid Dosage Forms: Solvent Activity
Critical quality attribute has been defined as “a physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality”. Deviations from preset quality metrics may potentially result in drug products with inferior therapeutic efficacy and unacceptable clinical safety profile. Topical cream formulations may possess numerous quality attributes that can affect the permeation of the drug through skin and consequently therapeutic efficacy. CQAs of topical formulations are often aimed at characterizing either the physicochemical properties of APIs or bulk characteristics of the formulation itself. Solvent systems constitute a major proportion of semisolid cream type formulations and its inclusion is critical to overall product performance (drug delivery to skin). A majority of the commercially available dermatological formulations contain solvent systems (water, ethanol, propylene glycol, glycerol and liquid chemical permeation enhancers) but the significance of solvent activity (thermodynamic solvent properties) on product performance has not been investigated so far, to be translated into a quality metric system (CQA). Water was utilized as a model solvent in order to link thermodynamic solvent activity and drug delivery performance of topical semi-solid cream systems. The overall aim of the research investigation is to evaluate water activity as a critical quality attribute of topical semi-solid dosage forms. Primary goal of this study was to investigate the mechanistic effects of water activity on drug release properties of formulation and drug permeation across the skin. A related objective was to investigate the mechanistic effects of water activity on skin hydration and barrier properties. For mechanistic investigation, a simple topical vehicle of varied aw (0.97 - 0.42) was formulated using deionized water with caffeine (model drug). Drug transport studies were performed using Franz diffusion cells across cellulose and silicone membrane (porous-hydrophilic and non-porous-hydrophobic membrane models, respectively) in order to elucidate the effects of water activity on drug release from formulation vehicles. Caffeine flux was found to decrease with decreasing water activity of the vehicle. The same trend was observed for drug release studies across all synthetic membranes tested. Series of dye diffusion study was designed to investigate bulk diffusion/release properties of caffeine (model solute) from water activity modulated topical formulations. Sucrose solution was utilized as viscosity control to decouple/delineate water activity effects on bulk solute diffusion. Caffeine diffusion was relatively slow in low water activity formulation vehicles versus to respective viscosity controls of same water activity (sucrose solution). In-vitro permeation studies were performed across porcine epidermis to investigate water activity effects on drug permeation across model skin membrane. Utilizing drugs of varied skin affinity (caffeine, acyclovir and nicotine) IVPT was performed across porcine epidermis under finite and infinite dosing conditions. Under both dosing conditions, caffeine, acyclovir and nicotine flux were found to reduce with lowering water activity of formulation vehicle. Also, the lag time for drug permeation increased with a decrease in water activity of solution formulation. Effects of low water activity on skin hydration were studied by placing vehicles of varied water activity on porcine skin equilibrated to ambient conditions (22°C/50% RH) and monitoring the changes gravimetrically. The hydration level measurement following exposure to different water activity formulations shothat the moisture content increases in the epidermis when hydrated with water, as expected. Notably, when exposed to lower water activity solutions, the epidermis would lose existing water, exhibiting an apparent dehydration effect. The histological evaluation revealed mild perturbation in the stratum corneum layer of the skin samples treated with lower water activity vehicles. This was potentially caused by osmotic shrinkage of corneocytes, which would be in agreement with the data from the hydration experiment. Role of hydrating agents (propylene glycol) on preservation of skin hydration, barrier properties and drug permeation was also investigated. Increasing levels of propylene glycol in low water activity vehicle (aw-0.78) enhanced drug flux across porcine epidermis. Notably, porcine skin treated with propylene glycol-aw 0.78 vehicle mixture (1:1) reverted stratum corneum perturbation caused by low water activity vehicle. Manufacturing process studies were undertaken to investigate effects of manufacturing process on water activity of topical cream (w/o type). Process parameters had profound impact on modulating water activity of a Q1/Q2 similar w/o type cream. Dynamic drying measurement revealed same water content in process prototypes. Based upon the results, water activity appears to be a potentially critical quality attribute for topical semisolid dosage forms, and may have the potential to influence the drug release from formulation as well as the permeation of the drug across the skin.
Critical Quality Attributes, Drug Release, Manufacturing Variabilities, Percutaneous Absorption, Solvent Activity, Topical Semi-Solid Dosage Forms, Pharmacy and Pharmaceutical Sciences
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