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PurposeTo efficiently develop a tablet formulation of carbamazepine using a soluble cocrystal with excess coformer to maintain phase stability during dissolution.Methods
The carbamazepine – glutaric acid cocrystal (CBZ-GLA, 1:1) and excess glutaric acid (GLA) were mixed with suitable tablet excipients, which were selected to address powder flowabil...
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Citations
... 153 A similar QbD approach has been reported in the development of tablet formulation of a carbamazepine−glutaric acid cocrystal with excess glutaric acid, considering flowability, tabletability, and carbamazepine dissolution rate as the critical quality attributes. 154 Further studies are required to investigate the potential of DoE and QbD in optimizing various processes during scale-up of solution-cocrystallization to enable reliable and successful product development at a large scale. Table 5 illustrates the Critical Quality Attributes (CQAs) of a cocrystal system that are influenced by different CPPs for solution-based cocrystallization techniques such as cooling, antisolvent addition, and slurry methods. ...
... The poor solubility of SOR in volatile solvents and its instability above the melting point (~212 • C, Table 1) exclude spray drying and HME as viable processes for preparing an ASD (Liu and Qian, 2015). Additionally, we adopted a material sparing and expedited tablet development approach guided by systematic characterization of powders and tablets using predictive tools (Wang et al., 2017a,b;Yamashita and Sun, 2020). ...
An amorphous solid dispersion (ASD) of sorafenib (SOR) in hydroxypropyl methylcellulose acetate succinate (HPMC-AS), prepared by coprecipitation, was used to develop an immediate release tablet with improved oral bioavailability. An ASD of 40% drug loading with HPMC-AS (M grade), which exhibited superior physical stability and enhanced dissolution, was selected for tablet development. Systematic characterization of powder properties of the ASD led to the choice of the dry granulation process to overcome poor flowability of the ASD. The designed tablet formulation was evaluated using a material-sparing and expedited approach to optimize compaction conditions for manufacturing ASD tablets with low friability and rapid disintegration. The resulting SOR ASD tablets exhibited approximately 50% higher relative bioavailability in dogs than the marketed SOR tablet product, Nexavar®.
... In the case of diphenhydramine, an ODT product that meets all requirements for commercial manufacturing was developed with 15 g of active pharmaceutical ingredient (API) in 2 months (Wang et al., 2017b). In a recent example, using the materials science based approach, 3 g of API and 3 weeks was used to develop an oral tablet formulation of carbamazepine (CBZ) using a glutaric acid cocrystal and a dry granulation process (Yamashita and Sun, 2020). In order for this development strategy to be broadly adopted during the preclinical stage of drug development, there is the need for more examples of expedited https://doi.org/10.1016/j.ijpharm.2020.119816 ...
The purpose of this work is to develop an orally disintegrating tablet (ODT) of sildenafil (SIL) using a materials sparing and expedited development approach, enabled by the materials science tetrahedron principle and predictive technologies. To overcome the problem of bitter taste of SIL, an artificial sweetener, acesulfame (Acs), was used to form a sweet SIL salt (SIL-Acs) using an effective reaction crystallization process to prepare phase pure bulk SIL-Acs with a high yield. The SIL-Acs salt shows excellent thermal stability (Tm = 200.2 oC), low hygroscopicity, and acceptable dissolution rate. Formulation and process parameters were optimized based on powder flowability, tabletability, tablet disintegration time, and expedited friability. A particle engineering approach, i.e., nanocoating, was employed to attain adequate flowability of the SIL-Acs ODT formulation required for the direct compression process. The wide range of compression forces for making tablets exhibiting both fast disintegration time (≤ 30 s) and low friability (≤0.8%) suggested excellent flexibility in manufacturing SIL-Acs ODT. The development of a sildenafil ODT formulation, including solid form selection and characterization, crystallization method development, formulation development, and DC process optimization, only required 5 g of SIL citrate and 2 weeks of time.
Unexpected cross-contamination by foreign components during the manufacturing and quality control of pharmaceutical products poses a serious threat to the stable supply of drugs and the safety of customers. In Japan, in 2020, a mix-up containing a sleeping drug went undetected by liquid chromatography during the final quality test because the test focused only on the main active pharmaceutical ingredient (API) and known impurities. In this study, we assessed the ability of a powder rheometer to analyze powder characteristics in detail to determine whether it can detect the influence of foreign APIs on powder flow. Aspirin, which was used as the host API, was combined with the guest APIs (acetaminophen from two manufacturers and albumin tannate) and subsequently subjected to shear and stability tests. The influence of known lubricants (magnesium stearate and leucine) on powder flow was also evaluated for standardized comparison. Using microscopic morphological analysis, the surface of the powder was observed to confirm physical interactions between the host and guest APIs. In most cases, the guest APIs were statistically detected due to characteristics such as their powder diameter, pre-milling, and cohesion properties. Furthermore, we evaluated the flowability of a formulation incorporating guest APIs for direct compression method along with additives such as microcrystalline cellulose, potato starch, and lactose. Even in the presence of several additives, the influence of the added guest APIs was successfully detected. In conclusion, powder rheometry is a promising method for ensuring stable product quality and reducing the risk of unforeseen cross-contamination by foreign APIs.
Whereas pharmaceutical co-crystals are widely described as tool to improve solubility and dissolution behavior of poorly soluble drugs, so far less focus has been on their potential role to facilitate pharmaceutical manufacturability. This review summarizes recent developments in co-crystal research regarding new trends in co-crystal preparation routes and control of solid-state material attributes. Also, recent literature was reviewed to assess risks for co-crystals in formulation processes. A growing number of publications suggest that co-crystals show potential to specifically improve mechanical properties such as tabletability and compressibility, which can often be linked to intrinsic features of crystal structure properties. However, such trends must be treated with care, as molecular structures in reported co-crystal studies are not representative in some structural parameters governing also solid-state behavior (smaller molecular weight, more balanced hydrogen bond donor versus acceptor counts) compared to recent market approved small molecule drugs. Teaser Pharmaceutical co-crystals should be considered more systematically as technology to overcome manufacturability issues of free forms and not solely as a tool to improve solubility constraints of drugs.
The impact of drug loading on the compaction properties of itraconazole (ITZ)- poly(vinylpyrrolidone-co-vinyl-acetate) (PVPVA) amorphous solid dispersions (ASDs) was studied. Neat amorphous ITZ, amorphous PVPVA, and their ASDs from 20% to 80% ITZ loadings were prepared by spray drying. Physical characterization showed that all powders have comparable particle size and morphology. All samples were equilibrated under 33% RH prior to compaction studies using a compaction simulator. Tabletability and compactability profiles of the ASD powders differed significantly, while their compressibility was similar. At compaction pressures from 50 to 150 MPa, tensile strength of ASD compacts increased with the increase of ITZ loading, reaching to the maximum at 40% - 60% ITZ loadings and then decreased as ITZ loading further increased. Whereas, at the compaction pressure of 200 MPa, a monotonic decrease of tensile strength with the increase of ITZ loading was observed. In addition, except for the ASD with 20% ITZ loading, the detrimental effect of compaction pressure on tensile strength was observed at pressures at or above 150 MPa. Overall, this work highlights the importance of evaluating the compaction properties of ASD intermediates prior to downstream tablet development, especially if a high drug loading ASD is desired.
Introduction
As an essential complement to chemically crosslinked macromolecular gels, drug delivery systems based on small molecular gels formed under the driving forces of non-covalent interactions are attracting considerable research interest due to their potential advantages of high structural functionality, lower biological toxicity, reversible stimulus-response and so on.
Area covered
The present review summarizes recent advances in small molecular gels and provides their updates as a comprehensive overview in terms of gelation mechanism, gel properties and physicochemical characterizations. In particular, this manuscript reviews the effects of drug based small molecular gels on the drug development and their potential applications in the pharmaceutical fields.
Expert opinion
Small molecular based gel systems, constructed by inactive compounds or active pharmaceutical ingredients, have been extensively studied as carriers for drug delivery in pharmaceutical field, such as oral formulations, injectable formulations and transdermal formulations. However, the construction of such gel systems yet faces several challenges such as rational and efficient design of functional gelators and the great occasionality of drug-based gel formation. Thus, a deeper understanding on the gelation mechanism and its relationship with gel properties will be conducive to the construction of small molecular gels systems and their future application.
Background
Quality by Design (QbD) is a pharmaceutical quality management system that predicts, controls, and systematically responds to risks that may occur in the research stage and manufacturing process. There are many articles on how to improve quality through application of the QbD system, but the methodology surrounding how to specifically apply this process is limited. The purpose of this review was to provide accurate information on drug development process and overcome the difficulties of developing QbD-applied drug products through an appropriate application method.Area coveredQbD-based pharmaceuticals are continuously being developed worldwide, helping to identify potential risks, and managing all aspects, from drug design to patient consumption, further enabling the patient to be administered a high-quality drugs based on their design. In this study, a basic knowledge of QbD, its application and effectiveness during drug development will be discussed.Expert opinionOur results suggest that a QbD for drug development can reduce risk to patients, improve drug quality, and continuously produce superior quality drug products.
Compared with clotrimazole, some multicomponent crystals showed an improvement in solubility and dissolution rate.
