Amorphous Solid Dispersion Formation for Enhanced Release Performance of Racemic and Enantiopure Praziquantel.

Praziquantel (PZQ) is the treatment of choice for schistosomiasis, which affects more than 250 million people globally. Commercial tablets contain the crystalline racemic compound (RS-PZQ) which limits drug dissolution and oral bioavailability and can lead to unwanted side effects and poor patient compliance due to the presence of the S-enantiomer. While many approaches have been explored for improving PZQ's dissolution and oral bioavailability, studies focusing on investigating its release from amorphous solid dispersions (ASDs) have been limited. In this work, nucleation induction time experiments were performed to identify suitable polymers for preparing ASDs using RS-PZQ and R-PZQ, the therapeutically active enantiomer. Cellulose-based polymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS, MF grade) and hydroxypropyl methylcellulose (HPMC, E5 LV grade), were the best crystallization inhibitors for RS-PZQ in aqueous media and were selected for ASD preparation using solvent evaporation (SE) and hot-melt extrusion (HME). ASDs prepared experimentally were subjected to X-ray powder diffraction to verify their amorphous nature and a selected number of ASDs were monitored and found to remain physically stable following several months of storage under accelerated-stability testing conditions. SE HPMCAS-MF ASDs of RS-PZQ and R-PZQ showed faster release than HPMC E5 LV ASDs and maintained good performance with an increase in drug loading (DL). HME ASDs of RS-PZQ formulated using HPMCAS-MF exhibited slightly enhanced release compared to that of SE ASDs. SE HPMCAS-MF ASDs showed a maximum release increase of the order of 6 times compared to generic and branded (Biltricide) PZQ tablets. More importantly, SE R-PZQ ASDs with HPMCAS-MF released the drug as effectively as RS-PZQ or better, depending on the DL used. These findings have significant implications for the development of commercial PZQ formulations comprised solely of the R-enantiomer, which can result in mitigation of the biopharmaceutical and compliance issues associated with current commercial tablets.

The importance of surface composition and wettability on the dissolution performance of high drug loading amorphous dispersion formulations.

One of the limitations with an amorphous solid dispersion (ASD) formulation strategy is low drug loading. Hydrophobic drugs have poor wettability and require a substantial amount of polymer to stabilize the amorphous drug and facilitate release. Using grazoprevir and hypromellose acetate succinate as model drug and polymer respectively, the interplay between particle surface composition, particle wettability, and release performance was investigated. A hierarchical particle approach was used where the surfaces of high drug loading ASDs generated by either solvent evaporation or co-precipitation were further modified with a secondary excipient (i.e., polymer or wetting agent). The surface-modified particles were characterized for drug release, wettability, morphology, and surface composition using two-stage dissolution studies, contact angle measurements, scanning electron microscopy, and X-ray photoelectron spectroscopy, respectively. Despite surface modification with hydrophilic polymers, hierarchical cPAD particles did not consistently exhibit good release performance. Contact angle measurements showed that the secondary excipient had a profound impact on particle wettability. Particles with good wettability showed improved drug release relative to particles that did not wet well, even with similar drug loadings. These observations underscore the intricate interplay between particle wettability and performance in amorphous dispersion formulations and illustrate a promising hierarchical particle approach to formulate high drug loading amorphous dispersions with improved dissolution performance.

Crystal Structure and Twisted Aggregates of Oxcarbazepine Form III.

Polymorphism and crystal habit play vital roles in dictating the properties of crystalline materials. Here, the structure and properties of oxcarbazepine (OXCBZ) form III are reported along with the occurrence of twisted crystalline aggregates of this metastable polymorph. OXCBZ III can be produced by crystallization from the vapor phase and by recrystallization from solution. The crystallization process used to obtain OXCBZ III is found to affect the pitch, with the most prominent effect observed from the sublimation-grown OXCBZ III material where the pitch increases as the length of aggregates increases. Sublimation-grown OXCBZ III follows an unconventional mechanism of formation with condensed droplet formation and coalescence preceding nucleation and growth of aggregates. A crystal structure determination of OXCBZ III from powder X-ray diffraction methods, assisted by crystal structure prediction (CSP), reveals that OXCBZ III, similar to carbamazepine form II, contains void channels in its structure with the channels, aligned along the c crystallographic axis, oriented parallel to the twist axis of the aggregates. The likely role of structural misalignment at the lattice or nanoscale is explored by considering the role of molecular and closely related structural impurities informed by crystal structure prediction.

Short-Term Assessment of the OHIP-14 Scale on Denture Wearers Using Adhesives.

PURPOSE: The purpose of this study was to assess differences of the Oral Health Implant Profile-14 (OHIP-14) scale over a month and determine association with gender, supporting tissues (KIS), and denture base (KID) among patients wearing complete dentures using denture adhesives. MATERIALS AND METHODS: Sixteen denture wearers, candidates for a new set of complete dentures, were selected. OHIP-14 scores were recorded at the beginning of the study, 6 weeks after fitting of the new set (T0 ), 15 days (T1 ), and finally 30 days (T2 ) after daily use of a denture adhesive as instructed. The KIS and KID were clinically examined and rated according to the Kapur Index. Statistical analyses were based on repeated-measures ANOVA, Mann-Whitney test, regression analysis, and Friedman test at a = 0.05. RESULTS: The OHIP-14 scale was found to have a high reliability (alpha = 0.847) and a high test-retest consistency (ICC = 0.889); however, domain 1 had the lowest item-total correlation (rho = 0.144) and item 7 a negative one (rho = -0.414). Trend analysis indicated a significant negative linear trend over time (slope = -3.156, p = 0.002), while repeated-measures ANOVA showed differences in OHIP-14 between T2 and T1 (p = 0.003) or T0 (p = 0.005) intervals. OHIP-14 groups were found to be positively associated with KIS (p = 0.010) and negatively with KID (p = 0.047) groups, but not with gender (p = 0.272). CONCLUSIONS: The study shows that OHIP-14 has a high internal reliability and consistency when applied to new denture wearers, and its score decreases if denture adhesives are used for at least 15 days. Low KIS and high KID contributes to this trend. Some OHIP-14 items are more associated than others with the total score trend over time.

Effect of adaptation time on the occlusal force at denture dislodgement with or without denture adhesive.

STATEMENT OF PROBLEM: The effect of denture adhesives on the occlusal forces at the dislodgement (OFD) of new complete dentures during the adaptation period has not been previously studied. PURPOSE: The purpose of this study was to investigate the OFD of dentures after their insertion and 3 months later, with or without denture adhesives. MATERIAL AND METHODS: Thirteen volunteers with edentulism were enrolled in the study. Each participant had new complete maxillary and mandibular dentures. The occlusal forces (N) at denture dislodgement were assessed with or without 2 adhesives by using an electronic gnathodynamometer in the incisal and premolar regions on the existing denture, the new denture immediately after fitting, 45 days later, and 90 days later. The statistical analysis included the Wilcoxon and Kruskal-Wallis tests, repeated measures ANOVA, and the Pearson coefficient at α=.05. RESULTS: Repeated measures ANOVA for new dentures showed that the OFD in the incisal or premolar region were significantly different between adaptation periods (P<.05) but not between adhesives. OFDs of dentures with and without adhesives correlated highly at all adaptation periods (0.912 to 0.995). CONCLUSIONS: The adaptation period does affect the OFD of new dentures, but the 2 adhesives were found to have the same effect on the OFD.