Specific mechanical energy - An essential parameter in the processing of amorphous solid dispersions.
TL;DR: A review of specific mechanical energy (SME) use in the pharmaceutical processing of amorphous solid dispersion (ASD) can be found in this article, along with the relative importance of thermal and mechanical input on various nonsolvent ASD processing methods.
About: This article is published in Advanced Drug Delivery Reviews.The article was published on 2021-03-27. It has received 13 citations till now.
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01 Dec 2021
TL;DR: An interesting heat- and shear-labile drug in development, LY3009120, and three compositionally identical formulations, suggest that the presence of some residual crystals after processing can be acceptable and will not change the properties of the ASD over time.
Abstract: We seek to further addresss the questions posed by Moseson et al. regarding whether any residual crystal level, size, or characteristic is acceptable in an amorphous solid dispersion (ASD) such that its stability, enhanced dissolution, and increased bioavailability are not compromised. To address this highly relevant question, we study an interesting heat- and shear-labile drug in development, LY3009120. To study the effects of residual crystallinity and degradation in ASDs, we prepared three compositionally identical formulations (57–1, 59–4, and 59–5) using the KinetiSol process under various processing conditions to obtain samples with various levels of crystallinity (2.3%, 0.9%, and 0.1%, respectively) and degradation products (0.74%, 1.97%, and 3.12%, respectively). Samples with less than 1% crystallinity were placed on stability, and we observed no measurable change in the drug's crystallinity, dissolution profile or purity in the 59–4 and 59–5 formulations over four months of storage under closed conditions at 25 °C and 60% humidity. For formulations 57–1, 59–4, and 59–5, bioavailability studies in rats reveal a 44-fold, 55-fold, and 62-fold increase in mean AUC, respectively, compared to the physical mixture. This suggests that the presence of some residual crystals after processing can be acceptable and will not change the properties of the ASD over time.
7 citations
TL;DR: In this paper , the authors used machine learning models to predict the amorphization of crystalline drug formulations and the chemical stability of subsequent ASDs prepared by the hot-melt extrusion (HME) process.
Abstract: Amorphous solid dispersion (ASD) is one of the most important strategies to improve the solubility and dissolution rate of poorly water-soluble drugs. As a widely used technique to prepare ASDs, hot-melt extrusion (HME) provides various benefits, including a solvent-free process, continuous manufacturing, and efficient mixing compared to solvent-based methods, such as spray drying. Energy input, consisting of thermal and specific mechanical energy, should be carefully controlled during the HME process to prevent chemical degradation and residual crystallinity. However, a conventional ASD development process uses a trial-and-error approach, which is laborious and time-consuming. In this study, we have successfully built multiple machine learning (ML) models to predict the amorphization of crystalline drug formulations and the chemical stability of subsequent ASDs prepared by the HME process. We utilized 760 formulations containing 49 active pharmaceutical ingredients (APIs) and multiple types of excipients. By evaluating the built ML models, we found that ECFP-LightGBM was the best model to predict amorphization with an accuracy of 92.8%. Furthermore, ECFP-XGBoost was the best in estimating chemical stability with an accuracy of 96.0%. In addition, the feature importance analyses based on SHapley Additive exPlanations (SHAP) and information gain (IG) revealed that several processing parameters and material attributes (i.e., drug loading, polymer ratio, drug's Extended-connectivity fingerprints (ECFP) fingerprints, and polymer's properties) are critical for achieving accurate predictions for the selected models. Moreover, important API's substructures related to amorphization and chemical stability were determined, and the results are largely consistent with the literature. In conclusion, we established the ML models to predict formation of chemically stable ASDs and identify the critical attributes during HME processing. Importantly, the developed ML methodology has the potential to facilitate the product development of ASDs manufactured by HME with a much reduced human workload.
4 citations
TL;DR: In this article, the authors show a promising strategy for maximizing the drug loading of pH-dependent APIs in amorphous solid dispersions (ASDs) produced by hot-melt extrusion without compromising their dissolution performance.
Abstract: Oral drug therapy requiring large quantities of active pharmaceutical ingredients (APIs) can cause a substantial pill burden, which can increase nonadherence and worsen healthcare outcomes. Maximizing the drug loading of APIs in oral dosage forms is essential to reduce pill burden. This can be challenging for poorly water-soluble APIs without compromising performance. We show a promising strategy for maximizing the drug loading of pH-dependent APIs in amorphous solid dispersions (ASDs) produced by hot-melt extrusion (HME) without compromising their dissolution performance. We examine potential increases in the drug loading (w/w) of telmisartan in ASDs by incorporating bases to modify pH during HME. Telmisartan is a weakly acidic, poorly water-soluble API with pH-dependent solubility. It is practically insoluble at physiological pH, but its solubility increases exponentially at pH values above 10. Telmisartan was extruded with the polymer Soluplus and various bases. With no base, the maximum drug loading achieved by extrusion was only 5% before crystalline telmisartan was detected. Including a strong, water-soluble base (NaOH or KOH) increased the maximum amorphous drug loading to 50%. These results indicate that telmisartan has pH-dependent solubility in a molten polymer, similar to that in an aqueous solution. We also examine the stability of Soluplus when extruded with a strong base, using solid-state nuclear magnetic resonance (ssNMR) to determine that NaOH (but not KOH) causes degradation by hydrolysis. Supersaturation was maintained for at least 20 h during dissolution testing of a 50% telmisartan ASD in biorelevant media.
3 citations
TL;DR: In this article , the effect of hydrolyzed protein meal from silage of trout (Oncorhynchus mykiss) on the parameters of the extrusion system and their physical transformations was investigated.
Abstract: Introduction The food industries play a fundamental role in feeding for the functions of animal metabolism. Fish feed extrusion cooking includes process-independent factors such as temperature (°C), screw speed (RPM), throughput, feed, and moisture content that influence the final product's nutritional value and physical properties. The evidence suggests that the application of hydrolyzed protein flour (HPH) is a crucial step for the techno-functional properties of the product. Therefore, this work aimed to study the effect of hydrolyzed protein meal from silage of trout (Oncorhynchus mykiss) on the parameters of the extrusion system and their physical transformations. Methods In this study, the influence of hydrolyzed protein meals ranges between 10 and 30% as a substitute for fish meals. The physical properties of the extrudate were monitored, evaluating the hardness, durability, buoyancy, expansion index, and apparent density. Results Consistent with this, parameters such as feed composition, screw speed, moisture content, and extrusion process affected the composition and properties of the final product. Discussion The physical properties indicated that the hydrolyzed protein flour presented cohesiveness and decreased the mean retention time in the extruder barrel and the specific mechanical energy (SME). Hydrolyzed protein flour during the extrusion process produces pellets with high durability and low hardness due to the high porosity presented, which allows for obtaining nutritional characteristics in the extruded product.
1 citations
TL;DR: In this paper , the authors developed a hypotensive supersaturating solid dispersion system (faSDDSHME) containing the BCS II drug, felodipine, when coordinately employing the HME technique and self-micellizing Soluplus®, and to characterize their amorphization as well as immediate release.
Abstract: The short-term immediate release of supersaturated drug-delivery systems (SDDSs) presents an interesting process that can be tailored to multi-stage release events including initial release after dosing and dissolution, evolved release over longer dissolution periods for biological absorption, and terminal release following the end of immediate release. However, although comprehensive analysis of these critical release behaviors is often ignored yet essential for understanding the supersaturable immediate-release events for supersaturable solid formations when employing new techniques or polymers matched to a particular API. Hot-melt extrusion (HME) has become a popular continuous thermodynamic disordering technique for amorphization. The self-micellizing polymer Soluplus® is reported to be a potential amorphous and amphiphilic graft copolymer frequently used in many nano/micro supersaturable formulations. Our current work aims to develop hypotensive supersaturating solid dispersion systems (faSDDSHME) containing the BCS II drug, felodipine, when coordinately employing the HME technique and self-micellizing Soluplus®, and to characterize their amorphization as well as immediate release. Other discontinuous techniques were used to prepare control groups (faSDDSSE and faSDDSQC). Tailored initial/evolved/terminal three-stage supersaturable immediate-release behaviors were identified and possible mechanisms controlling the release were explored. HME produced the highest initial release in related faSDDSHME. During the evolved-release period, highly extended “spring-parachute” process was found in HME-induced amorphization owing to its superior supersaturation duration. Due to the enhanced crystallization inhibition effect, faSDDSHME displayed the strongest terminal release as measured by solubility. For release mechanisms associated with HME, molecular interaction is not the likely dominant mechanism responsible for the improved properties induced by faSDDSHME. For release mechanisms involved with the polymer Soluplus® itself, they were found to inhibit drug recrystallization, spontaneously solubilize the drug and lead to improved molecular interactions in all SDDS systems, which were the factors responsible for the improved release. These mechanisms play an important role for the generation of an extended multi-stage immediate release produced via HME or self-micellizing polymer. This study provides a deeper understanding on amorphization and superior multi-stage supersaturable immediate-release behaviors for a particular hypotensive supersaturated delivery system combined with an HME-based continuous manufacturing technique and self-micellizing polymer strategy.
1 citations
References
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TL;DR: In this paper, the effect of the concentration on the rate at which a solid substance dissolves in its own solution, has not heretofore been investigated, probably due to the experimental difficulties in the way of keeping the surface of the dissolving substance constant during the solution.
Abstract: As far as we know, the effect of the concentration on the rate at which a solid substance dissolves in its own solution, has not heretofore been investigated. This is probably due to the experimental difficulties in the way of keeping the surface of the dissolving substance constant during the solution.
1,653 citations
TL;DR: In this article, it was shown that the non-Gaussian-Markoff process for Brownian motion derived on a statistical mechanical basis by Prigogine and Balescu, and Prigogueine and Philippot, is related through a transformation of variables to the Gaussian Markoff process of the conventional phenomenological theory of Brownian motions.
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929 citations
TL;DR: Experimental models which allow for more quantitative estimates of the thermodynamics of mixing amorphous drugs with glassy polymers provide insight into the physical stability of drug–polymer mixtures and the thermodynamic driving force for crystallization.
Abstract: The amorphous form of a drug may provide enhanced solubility, dissolution rate, and bioavailability but will also potentially crystallize over time. Miscible polymeric additives provide a means to increase physical stability. Understanding the miscibility of drug–polymer systems is of interest to optimize the formulation of such systems. The purpose of this work was to develop experimental models which allow for more quantitative estimates of the thermodynamics of mixing amorphous drugs with glassy polymers. The thermodynamics of mixing several amorphous drugs with amorphous polymers was estimated by coupling solution theory with experimental data. The entropy of mixing was estimated using Flory–Huggins lattice theory. The enthalpy of mixing and any deviations from the entropy as predicted by Flory–Huggins lattice theory were estimated using two separate experimental techniques; (1) melting point depression of the crystalline drug in the presence of the amorphous polymer was measured using differential scanning calorimetry and (2) determination of the solubility of the drug in 1-ethyl-2-pyrrolidone. The estimated activity coefficient was used to calculate the free energy of mixing of the drugs in the polymers and the corresponding solubility. Mixtures previously reported as miscible showed various degrees of melting point depression while systems reported as immiscible or partially miscible showed little or no melting point depression. The solubility of several compounds in 1-ethyl-2-pyrrolidone predicts that most drugs have a rather low solubility in poly(vinylpyrrolidone). Miscibility of various drugs with polymers can be explored by coupling solution theories with experimental data. These approximations provide insight into the physical stability of drug–polymer mixtures and the thermodynamic driving force for crystallization.
459 citations
TL;DR: Combining calculation of Hansen solubility parameters with thermal analysis of drug/excipient miscibility can be successfully applied to predict formation of glass solutions with melt extrusion.
396 citations