(M1530-01-02) Simultaneous XRD-DSC Analysis Identifies Correct Solid Form Dissolution in Polymer

Purpose: Amorphous solid dispersions (ASD) are emerging as a preferred formulation strategy for poorly water-soluble drugs, allowing improvement in drug apparent aqueous solubility with commensurate opportunities for physical stabilization. Polymer screening is the first step in ASD development, which usually requires estimation of drug solubility in prospective polymer carriers. Conventionally, differential scanning calorimetry (DSC) is used to measure the dissolution of the drug in the polymer, however, molecules having polymorphs with difficult-to-resolve melting temperatures (T_m), that may also undergo solid-state interconversions on heating, can result in incorrect solubility determinations. In the present research, the application of simultaneous XRD-DSC was investigated as a means of determining the solubility of the form of interest in the polymer.

Methods: A well-established dissolution endpoint (T_end) method was used to evaluate the solubility of 4-bromo-N-(propylcarbamoyl) benzenesulfonamide (i.e., bromopropamide) in the co-polymer polyvinylpyrrolidone vinylacetate (PVPVA). Physical mixtures of bromopropamide and PVPVA with co-polymer concentrations ranging from 0 to 50 %w/w were cryomilled for total milling times of 10 – 60 min. Simultaneous XRD-DSC measurements were performed using a SmartLab XRD instrument (Rigaku Co., Tokyo, Japan) with a directly integrated heat-flux type DSC unit. Milled samples weighing between 10 – 15 mg were placed on an aluminum DSC pan and the DSC unit was used to heat the samples at 1 °C/min to 150 °C to determine the T_end. During all experiments, the sample environment was maintained at < 5% RH using a humidity controller. The XRD experiments were conducted simultaneously with the DSC analysis by irradiating the samples with Cu Kα X-rays (λ = 1.5406 Å) generated at 45 kV and 200 mA. Diffraction data were collected over the range of 7 – 33 °2θ at an integrated step size of 0.02 °2θ at a rate of 10 °2θ/min.

Results: When heated at 1 °C/min, the low-temperature stable enantiotrope of bromopropamide (form-1) melted at T_m,endpoint = 133 °C, followed by recrystallization to the high-temperature stable enantiotrope (form-2), which then melted at T_m,endpoint = 140 °C. XRD patterns were collected simultaneously during heating for each form of bromopropamide and the resulting diffractograms were used to confirm or identify the T_end for the corresponding polymorphs in PVPVA. The addition of increasing quantities of PVPVA to bromopropamide resulted in a reduction of T_end to lower temperatures for both forms. At higher PVPVA concentrations, the DSC heat flow signal was suppressed for form-2 relative to form-1. When polymer concentrations >20 %w/w were used, the heat flow signal for form-2 was undetectable. Simultaneous XRD measurements, however, revealed that form-1 dissolved and then recrystallized as form-2 in the PVPVA matrix, which then dissolved in the co-polymer. Simultaneous XRD-DSC aided in confidently measuring the T_end for bromopropamide form-2 across multiple PVPVA concentrations (Figure 1). Additionally, XRD-DSC helped to determine the T_end for form-1 in PVPVA, concurrently with that for form-2 (Figure 1). Notably, the changes in T_end with respect to increasing PVPVA were higher for form-2 compared to form-1, although it has a lower T_m. Owing to a higher melting enthalpy (ΔH_m) for form-1, however, its solubility in PVPVA was found to be lower (20.95 %w/w) at 25 °C relative to that of form-2 (25.65 %w/w). Furthermore, integration of these techniques allowed identification of the polymer concentration above which the conversion of form-1 to form-2 was kinetically restricted, even on heating to higher temperatures.

Conclusion: Polymer selection is a critical step in successful ASD formulation development, where drug-in-polymer solubility measurements are used to identify the equilibrium drug-polymer solution concentration at a given temperature. Identification of the solubility limit defines the maximum drug-loading achievable or helps to estimate the supersaturation ratios, which can further inform the shelf-life of the ASD. Drug molecules that have multiple polymorphs with similar T_m that undergo solid-form transitions on heating can increase the complexity, or possibly mislead the measurement of drug-polymer dissolution temperatures, if characterized using only DSC. The application of simultaneous XRD-DSC not only allowed solubility determination for bromopropamide form-2 in PVPVA, it also permitted concomitant dissolution measurement for the form-1 polymorph. XRD-DSC also assisted with identifying the polymer concentration at which the form interconversion was kinetically inhibited. Owing to its analytical flexiblity, simultaneous XRD-DSC can help select a polymer for ASD development effectively and accelerate the ASD development process.

Acknowledgements: The authors would like to thank Rigaku Americas Corporation for financial support.

Figure 1: Temperature-composition phase diagram showing experimental dissolution endpoints for bromopropamide form-2 and form-1 in polymer PVPVA. The predicted solubility solid line is obtained using the van’t Hoff relationship. The dashed line indicates the glass transition temperature of the drug-polymer dispersion predicted using the Couchman-Karasz equation. Error bars are smaller than the size of the markers.