Non-Sink Dissolution Conditions for Predicting Product Quality and In Vivo Performance of Supersaturating Drug Delivery Systems

Sun, Dajun; Wen, Hu; Taylor, Lynne S.

doi:10.1016/j.xphs.2016.03.024

Cited by 111 publications

(80 citation statements)

References 89 publications

(99 reference statements)

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“…Dissolution methods under non-sink conditions are commonly used for evaluating the ability of poorly soluble APIs to generate and to maintain a supersaturation state in solution [24,39]. Additionally, Pharmaceutics 2020, 12, 23 3 of 18 powder dissolution experiments are a good alternative to intrinsic dissolution tests for cocrystals undergoing rapid transformation to a less soluble phase of the drug [24], as recently found in the biopharmaceutical characterization of cocrystals with meloxicam, indomethacin, apixaban and myricetin [40][41][42][43].…”

Section: Introductionmentioning

confidence: 99%

Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

et al. 2019

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The effect of hydroxypropyl methylcellulose (HPMC) and methylcellulose (Methocel ® 60 HG) on the dissolution behavior of two cocrystals derived from nitazoxanide (NTZ), viz., nitazoxanide-glutaric acid (NTZ-GLU, 1:1) and nitazoxanide-succinic acid (NTZ-SUC, 2:1), was explored. Powder dissolution experiments under non-sink conditions showed similar dissolution profiles for the cocrystals and pure NTZ. However, pre-dissolved cellulosic polymer in the phosphate dissolution medium (pH 7.5) modified the dissolution profile of NTZ when starting from the cocrystals, achieving transient drug supersaturation. Subsequent dissolution studies under sink conditions of polymer-based pharmaceutical powder formulations with NTZ-SUC cocrystals gave a significant improvement of the apparent solubility of NTZ when compared with analogous formulations of pure NTZ and the physical mixture of NTZ and SUC. Scanning electron microscopy and powder X-ray diffraction analysis of samples recovered after the powder dissolution studies showed that the cocrystals undergo fast dissolution, drug supersaturation and precipitation both in the absence and presence of polymer, suggesting that the solubilization enhancement is due to polymer-induced delay of nucleation and crystal growth of the less soluble NTZ form. The study demonstrates that the incorporation of an appropriate excipient in adequate concentration can be a key factor for inducing and maintaining the solubilization of poorly soluble drugs starting from co-crystallized solid forms. In such a way, cocrystals can be suitable for the development of solid dosage forms with improved bioavailability and efficacy in the treatment of important parasitic and viral diseases, among others.

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Section: Introductionmentioning

confidence: 99%

Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

et al. 2019

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“…The dissolution profile of pure crystalline CDP146 was obtained in each dissolution medium so that the solubility improvement (%) of screened SDSD can be evaluated. The aforementioned dissolution conditions represent non-sink conditions with respect to the crystalline drug so that the ability of screened ASD to generate and maintain supersaturation can be assessed during the duration of the test [ 34 ]. Dissolution tests were carried out manually in 10 mL glass tube (VWR, Heverlee, Belgium).…”

Section: Methodsmentioning

confidence: 99%

A Novel Protocol Using Small-Scale Spray-Drying for the Efficient Screening of Solid Dispersions in Early Drug Development and Formulation, as a Straight Pathway from Screening to Manufacturing Stages

et al. 2018

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This work describes a novel screening strategy that implements small-scale spray-drying in early development of binary amorphous solid dispersions (ASDs). The proposed methodology consists of a three-stage decision protocol in which small batches (20–100 mg) of spray-dried solid dispersions (SDSDs) are evaluated in terms of drug–polymer miscibility, physical stability and dissolution performance in bio-predictive conditions. The objectives are to select the adequate carrier and drug-loading (DL) for the manufacturing of robust SDSD; and the appropriate stabilizer dissolved in the liquid vehicle of SDSD suspensions, which constitutes the common dosage form used during non-clinical studies. This methodology was verified with CDP146, a poorly water soluble (<2 µg/mL) API combined with four enteric polymers and four stabilizers. CDP146/HPMCAS-LF 40:60 (w/w) and 10% (w/v) PVPVA were identified as the lead SDSD and the best performing stabilizer, respectively. Lead SDSD suspensions (1–50 mg/mL) were found to preserve complete amorphous state during 8 h and maintain supersaturation in simulated rat intestinal fluids during the absorption window. Therefore, the implementation of spray-drying as a small-scale screening approach allowed maximizing screening effectiveness with respect to very limited API amounts (735 mg) and time resources (9 days), while removing transfer steps between screening and manufacturing phases.

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“…Early in development, a variety of explorative approaches (i.e., dissolution in biorelevant media (23), multi-stage dissolution (24,25), biphasic/multicompartmental (gastro-intestinal models) (26), dissolution in non-sink conditions, etc.) or dissolution in multi-pH media can be used to evaluate the possible impact of formulation and process factors on the in vivo performance of the dosage form.…”

Section: Clinically Relevant Specification Roadmapmentioning

confidence: 99%

Approaches for Establishing Clinically Relevant Dissolution Specifications for Immediate Release Solid Oral Dosage Forms

Hermans

Abend

Kesisoglou

et al. 2017

AAPS J

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Abstract.This manuscript represents the perspective of the Dissolution Analytical Working Group of the IQ Consortium. The intent of this manuscript is to highlight the challenges of, and to provide a recommendation on, the development of clinically relevant dissolution specifications (CRS) for immediate release (IR) solid oral dosage forms. A roadmap toward the development of CRS for IR products containing active ingredients with a non-narrow therapeutic window is discussed, within the context of mechanistic dissolution understanding, supported by in-human pharmacokinetic (PK) data. Two case studies present potential outcomes of following the CRS roadmap and setting dissolution specifications. These cases reveal some benefits and challenges of pursuing CRS with additional PK data, in light of current regulatory positions, including that of the US Food and Drug Administration (FDA), who generally favor this approach, but with the understanding that both industry and regulatory agency perspectives are still evolving in this relatively new field. The CRS roadmap discussed in this manuscript also describes a way to develop clinically relevant dissolution specifications based primarily on dissolution data for batches used in pivotal clinical studies, acknowledging that not all IR product development efforts need to be supported by additional PK studies, albeit with the associated risk of potentially unnecessarily tight manufacturing controls. Recommendations are provided on what stages during the life cycle investment into in vivo studies may be valuable. Finally, the opportunities for CRS within the context of post-approval changes, Modeling and Simulation (M&S), and the application of biowaivers, are briefly discussed.KEY WORDS: BCS; biowaivers; clinically relevant dissolution specifications; PBPK modeling; SUPAC.This article was developed with the support of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org). IQ is a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators, and the broader research and development community. PURPOSEThe purpose of this paper is to describe a roadmap for the development and leverage of clinically relevant dissolution specifications (CRS) for immediate release oral solid dosage forms of non-narrow therapeutic window drugs. There are three objectives for presenting this roadmap: (1) to describe multiple approaches for establishing clinical relevance for dissolution methodology, (2) to outline how to leverage clinically relevant dissolution methodology and specifications for the confirmation of the final drug product quality, and (3) to suggest recommendations on supporting scale-up and post-approval changes using the established CRS.Historically, dissolution specifications have been set by controlling the formulation and process within prec...

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Non-Sink Dissolution Conditions for Predicting Product Quality and In Vivo Performance of Supersaturating Drug Delivery Systems

Cited by 111 publications

References 89 publications

Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

A Novel Protocol Using Small-Scale Spray-Drying for the Efficient Screening of Solid Dispersions in Early Drug Development and Formulation, as a Straight Pathway from Screening to Manufacturing Stages

Approaches for Establishing Clinically Relevant Dissolution Specifications for Immediate Release Solid Oral Dosage Forms

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