Research PaperEnabling thermal processing of ritonavir–polyvinyl alcohol amorphous solid dispersions by KinetiSol® Dispersing
Graphical abstract
Introduction
Thermal processing methods, such as hot-melt extrusion (HME), continue to be an active area of research and commercial interest in the pharmaceutical industry [1], [2]. In particular, the range of amorphous solid dispersion (ASD) platforms driven by polymer carriers is expanding and continues to be optimized [3], [4]. However, thermal processing of many compositions can be challenging due to thermal degradation, viscoelastic properties, or disparities between the active ingredient and excipient temperature processing windows [5]. This can lead to a compromise between manufacturing capability and selection of the optimal formulation composition. Given polymer carriers are often the driving force for determining the performance of an ASD to inhibit crystallization in the solid [6], [7] and solution [8], [9] states, as well as controlling the release properties to match the desired product profile [10], [11], enabling processing of the widest range of carriers is desirable.
One such polymer that has been difficult to thermally process into an ASD while offering a diverse range of properties by grade is polyvinyl alcohol (PVA). PVA is typically a semi-crystalline polymer that is available in a range of grades that vary by the degree of hydrolysis, a measure of the ratio of polyvinyl alcohol to polyvinyl acetate groups, and degree of polymerization [12]. Only grades that contain a majority of polyvinyl acetate groups are fully amorphous. The ratio of alcohol groups to acetate groups, which affects the degree of crystallinity, greatly influences the solubility and swellability of the polymer [13], which in turn can impact the release properties when formulated into a drug product. For physical stabilization in ASDs, the ratio of alcohol to acetate groups dictates the number of hydrogen bond donor groups (hydroxyl) as well as the number of hydrophobic groups (acetate), which is important given various researchers have shown that both hydrogen bonding and hydrophobic interactions between drugs and polymers can impact physical stability in the solid and solution state [14], [15].
The reason that PVA has been difficult to process by thermal methods such as HME is twofold. First, semicrystalline PVA remains solid-like below its melting point and is thus not extrudable below this temperature [16], [17]. Second, PVA is thermally sensitive and degrades near its melting point through elimination of hydroxyl and acetate side groups, forming water and acetic acid as shown in Scheme 1, with acetic acid further catalyzing the degradation process [18], [19]. Interestingly, a recent study evaluated PVA in extrusion processing, requiring processing temperatures at the melting point (∼180 °C) for partially hydrolyzed PVA, but no evaluation of polymer degradation was performed [20], though the study did highlight the exclusion of APIs that are thermally labile below the processing temperature. Elimination of side groups is clearly undesirable given their impact on drug product properties as previously described. Attempts to process PVA by extrusion, film blowing, and injection molding have required the use of plasticizers or other additives to depress the melting point and melt viscosity of PVA [21], [22], with such methods achieving limited success in fully eliminating polymer degradation [23]. The incorporation of additives may be undesirable in ASDs, however, due to potential impacts on physical stability and release properties [24], [25].
KinetiSol® Dispersing (KSD) is an emerging thermal processing technology in the pharmaceutical industry [26]. The process consists of a chamber with a central rotating shaft containing a series of mixing blades. The shaft rotates at relatively high velocities (1000’s of RPMs), imparting high frictional energy from particle impaction, which results in very rapid temperature increases with total processing times typically less than 20 s. Notably, no external heating is applied in the process. The process has enabled manufacturing of ASDs without the use of plasticizers [25], including non-thermoplastic polymers and thermally labile polymers [27]. Given the ability of KSD to process non-thermoplastic polymers with very short residence times, we hypothesized that this technology could be used to form amorphous solid dispersions of PVA at temperatures below its melting point with minimal or no side chain elimination. We have previously evaluated KSD processing of PVA with itraconazole [28], but several questions remain unanswered including a thorough understanding of the relative impact of KSD processing parameters on the physical and chemical stability of the drug and polymer. While size exclusion chromatography (SEC) was previously utilized to investigate the impact of processing on the apparent polymer molecular weight and no decrease in apparent molecular weight was observed [28], a deeper investigation of side chain elimination of PVA is warranted.
The aims of this study were to understand the impact of KSD processing parameters in order to produce an ASD with minimal to no degradation of the polymer and model API. Ritonavir was chosen as the model API as it is commercially processed as an ASD by HME in Kaletra®, Norvir®, and Viekirax® [29], [30]. Additionally, ritonavir has been shown to be shear sensitive [31], thus representing a challenging model in the KSD process, which exhibits much higher shear rates compared to HME.
Section snippets
Materials
Polyvinyl alcohol 4-88 (PVA 4-88, Art. No.141350, EMPROVE® exp Ph Eur, USP, JPE) was kindly donated by MilliporeSigma (MilliporeSigma is a business of Merck KGaA, Darmstadt, Germany). Kollidon PVP VA64 was kindly donated by BASF The Chemical Company (Florham Park, NJ, USA). Ritonavir (>98% purity) was purchased from Shengda Pharmaceutical Company Limited (Shenzhen, China). High performance liquid chromatography grade acetonitrile, methanol, and water were purchased from Fisher Scientific
Preformulation characterization
Thermogravimetric analysis was used to investigate the onset of thermal degradation for each of the formulation components. PVA exhibited an initial weight loss up to 100 °C, which was attributed to the loss of water, followed by a more significant weight loss due to polymer degradation after the melting point, as shown in Fig. 1. Ritonavir was stable up to a temperature of approximately 160 °C, with an approximately 40% weight loss between 160 °C and 220 °C. Ritonavir was also shown to be the
Discussion
The objective of this study was to thermally process an ASD using the model compound ritonavir with PVA as the carrier, while maintaining acceptable stability of both the drug and polymer. The TGA and rheology data illustrate the challenges of thermally processing the studied composition into an ASD by common processes such as HME. The thermal degradation temperature of ritonavir (160 °C) establishes the maximum processing temperature. Below 160 °C, the complex viscosity of the composition
Conclusion
Use of polymers such as PVA in pharmaceutical thermal processes such as HME has often been limited due to the thermal and viscoelastic properties of the polymer, which can require high processing temperatures. Depending on residence time, this can result in significant degradation of the polymer and more importantly is completely unviable in cases where the API degrades below the minimum processing temperature of the polymer. Here, we have shown that a drug-polymer composition representing such
Acknowledgments
The authors would like to gratefully acknowledge the financial support by EMD (Merck) Millipore. The authors would also like to acknowledge Lindsey Sharpe for her assistance with rheology testing, Jordan Dinser for her assistance with LC/MS testing, and Steve Sorey for his assistance with NMR testing.
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