Abstract
The objective of this study was to develop an immediate release (IR), crystalline solid dispersion (CSD) formulation of Mefenamic acid (MFA) by hot-melt-extrusion (HME) and assess the impact of drug loading on process parameters, product physico-chemical properties and product performance. An HME process to produce a range of MFA-Soluplus®-Sorbitol polymer matrix CSD formulations was developed based on rheological screening assays of physical mixtures (PM). The impact of drug loading on process parameters was compared to the impact of drug loading on the physico-chemical properties of formulations. Based on process and product data, three groupings of API drug loading were identified: sub-saturated, saturated, and supersaturated systems. CSD formulations were obtained for 20–50% (w/w) drug loading containing the stable polymorphic form I of MFA. CSD formulations predominantly improved the consistency of the product performance. An Amorphous Solid Dispersion (ASD) was obtained for 10% (w/w) drug loading, exhibiting faster drug release even at physiologically relevant pH. This study illustrates the impact of drug loading on process and product characteristics and how a better understanding of maximum API solubility in a given polymer system can improve targeted formulation development.
Highlights
Mefenamic acid is a nonsteroidal anti-inflammatory drug and is used to treat mild to moderate pain
The behaviour of the formulation in the process and product was related to the ratio of drug loading to maximum solubility of the API in the polymer matrix and was grouped into three broad categories of: a) sub-saturated, b) saturated, and c) super-saturated systems (Table 3)
The application of rheology screening to the HME process development facilitated detection of appropriate processing conditions, needing less material
Summary
Mefenamic acid is a nonsteroidal anti-inflammatory drug and is used to treat mild to moderate pain. MFA is classed as a BCS class IIa drug (Butler and Dressman, 2010; Nurhikmah et al, 2016), showing poor solubility and high permeability, and dissolution rate limited (Butler and Dressman, 2010) absorption of the drug into the body. For dissolution rate limited drugs, formulation approaches carefully need to consider the polymorphic form (Romero et al, 1999), particle size, surface area and wettability of the drug to achieve complete oral absorption (Butler and Dressman, 2010; Vasconcelos et al, 2007). Three crystalline forms have been published for MFA, with form I the most stable at ambient temperature (Surov et al, 2009). Upon heating MFA form I, phase transition of the stable form can occur via sublimation (Brittain, 2016; SeethaLekshmi and Guru Row, 2012; Surov et al, 2009)
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