Role of polymers in the physical and chemical stability of amorphous solid dispersion: A case study of carbamazepine

Woo

et al. 2022

IJMS

The purpose of this study was to investigate the efficacy of hydrophilic polymers in a solid dispersion formulation in improving the solubility and dissolution rate of rivaroxaban (RXB), a poorly soluble drug. The developed solid dispersion consisted of two components, a drug and a polymer, and the drug was dispersed as amorphous particles in a polymer matrix using the spray drying method. Polymeric solid dispersions were evaluated using solubility tests, in vitro dissolution tests, powder X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and particle size distribution analysis. To maximize physical stability against crystallization and improve the solubility and dissolution of RXB, it is important to select the appropriate polymer type and the optimal ratio of the polymer to the drug. The optimized polyvinyl alcohol (PVA)-based (1/0.5, w/w) and gelatin-based (1/5, w/w) solid dispersion formulations showed 6.3 and 3.6 times higher drug solubilities than pure RXB powder, respectively, and the final dissolution rate was improved by approximately 1.5 times. Scanning electron microscopy and particle size distribution analyses confirmed that the gelatin-based solid dispersion was smaller and more spherical than the PVA-based solid dispersion, suggesting that the gelatin-based solid dispersion had a faster initial dissolution rate. Differential scanning calorimetry and powder X-ray diffraction analyses confirmed that RXB had successfully changed from a crystalline form to an amorphous form, contributing to the improvement in its solubility and dissolution rate. This study provides a strategy for selecting suitable polymers for the development of amorphous polymer solid dispersions that can overcome precipitation during dissolution and stabilization of the amorphous state. In addition, the selected polymer solid dispersion improved the drug solubility and dissolution rate of RXB, a poorly soluble drug, and may be used as a promising drug delivery system.

Section: Resultsmentioning

confidence: 99%

“…PXRD was performed using a diffractometer (D/MAX-2500; Rigaku, Tokyo, Japan) with monochromatic Cu Kα radiation (γ = 1.54178 Å) [ 33 ]. The X-ray generator settings were 40 kV and 100 mA.…”

Section: Methodsmentioning

confidence: 99%

Effects of Polymers on the Drug Solubility and Dissolution Enhancement of Poorly Water-Soluble Rivaroxaban

Woo

et al. 2022

IJMS

“…Currently, the most common strategy for preserving the recrystallization of amorphous APIs, is to disperse them into a polymeric matrix molecularly, i.e., prepare an amorphous solid dispersion (ASD) [ 19 , 20 , 21 ]. It is generally recognized that the role of the polymer in an ASD is to reduce molecular mobility, inhibit the nucleation and crystal growth of amorphous active material, and facilitate its release from the polymeric matrix [ 22 , 23 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Hot Melt Extruded Posaconazole-Based Amorphous Solid Dispersions—The Effect of Different Types of Polymers

et al. 2023

Four model polymers, representing (i) amorphous homopolymers (Kollidon K30, K30), (ii) amorphous heteropolymers (Kollidon VA64, KVA), (iii) semi-crystalline homopolymers (Parteck MXP, PXP), and (iv) semi-crystalline heteropolymers (Kollicoat IR, KIR), were examined for their effectiveness in creating posaconazole-based amorphous solid dispersions (ASDs). Posaconazole (POS) is a triazole antifungal drug that has activity against Candida and Aspergillus species, belonging to class II of the biopharmaceutics classification system (BCS). This means that this active pharmaceutical ingredient (API) is characterized by solubility-limited bioavailability. Thus, one of the aims of its formulation as an ASD was to improve its aqueous solubility. Investigations were performed into how polymers affected the following characteristics: melting point depression of the API, miscibility and homogeneity with POS, improvement of the amorphous API’s physical stability, melt viscosity (and associated with it, drug loading), extrudability, API content in the extrudate, long term physical stability of the amorphous POS in the binary drug–polymer system (in the form of the extrudate), solubility, and dissolution rate of hot melt extrusion (HME) systems. The obtained results led us to conclude that the physical stability of the POS-based system increases with the increasing amorphousness of the employed excipient. Copolymers, compared to homopolymers, display greater homogeneity of the investigated composition. However, the enhancement in aqueous solubility was significantly higher after utilizing the homopolymeric, compared to the copolymeric, excipients. Considering all of the investigated parameters, the most effective additive in the formation of a POS-based ASD is an amorphous homopolymer—K30.

“…Carbamazepine (CBZ) is an anticonvulsant drug used primarily in the treatment of epilepsy and neuropathic pain. Several physical forms of this compound have been reportedpolymorphs of anhydrate {CBZ Form I (or γ-), II, III (or β), and IV}, amorphous form (glass-transition temperature ( T g ) of 53 °C), and a dihydrate. , Anhydrous form III is the most stable form at room temperature. The crystal structures of all of these solid forms have been determined .…”

Section: Introductionmentioning

confidence: 99%

Drug Phase Transformation and Water Redistribution during Continuous Tablet Manufacturing: A Case Study of Carbamazepine Dihydrate

et al. 2023

In recent years, continuous tablet manufacturing technology has been used to obtain regulatory approval of several new drug products. While a significant fraction of active pharmaceutical ingredients exists as hydrates (wherein water is incorporated stoichiometrically in the crystal lattice), the impact of processing conditions and formulation composition on the dehydration behavior of hydrates during continuous manufacturing has not been investigated. Using powder X-ray diffractometry, we monitored the dehydration kinetics of carbamazepine dihydrate in formulations containing dibasic calcium phosphate, anhydrous (DCPA), mannitol, or microcrystalline cellulose. The combined effect of nitrogen flow and vigorous mixing during the continuous mixing stage of tablet manufacture facilitated API dehydration. Dehydration was rapid and most pronounced in the presence of DCPA. The dehydration product, amorphous anhydrous carbamazepine, sorbed a significant fraction of the water released by dehydration. Thus, the dehydration process resulted in a redistribution of water in the powder blend. The unintended formation of an amorphous dehydrated phase, which tends to be much more reactive than its crystalline counterparts, is of concern and warrants further investigation.