Comparison of induction methods for supersaturation: pH shift versus solvent shift

Plum, Jakob; Bavnhøj, Christoffer G.; Palmelund, Henrik; Pérez‐Alós, Laura; Müllertz, Anette; Rades, Thomas

doi:10.1016/j.ijpharm.2019.118862

Cited by 7 publications

(5 citation statements)

References 34 publications

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“…Ketoconazole is the first Imidazole antifungal drug that can be taken orally and is widely used in superficial and systemic fungal infections [23]. Ketoconazole is also used in castration-resistant prostate cancer because it inhibits CYP17A1, which is involved in the production of sex hormones, and blocks both gonadal and adrenal steroid hormone synthesis [24]. Ketoconazole has been used as the model drug for 47 supersaturation-related studies (data from PubMed until 1 October 2023) because ketoconazole is a classical BCS IIB drug that is rather soluble in acidic gastric fluid but precipitates in the human upper intestine [25].…”

Section: Ivivcmentioning

confidence: 99%

Revisiting Supersaturation of a Biopharmaceutical Classification System IIB Drug: Evaluation via a Multi-Cup Dissolution Approach and Molecular Dynamic Simulation

Gan,

Xu,

Zhang

et al. 2023

Molecules

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As a subclass of the biopharmaceutical classification system (BCS) class II, basic drugs (BCS IIB) exhibit pH-dependent solubility and tend to generate supersaturation in the gastrointestinal tract, leading to less qualified in vitro–in vivo correlation (IVIVC). This study aims to develop a physiologically based multi-cup dissolution approach to improve the evaluation of the supersaturation for a higher quality of IVIVC and preliminarily explores the molecular mechanism of supersaturation and precipitation of ketoconazole affected by Polyvinylpyrrolidone–vinyl acetate copolymer (PVPVA) and hydroxypropyl methyl-cellulose (HPMC). The concentration of ketoconazole in each cup of the dynamic gastrointestinal model (DGIM) was measured using fiber optical probes. Molecular interactions between ketoconazole and PVPVA or HPMC were simulated by Materials Studio. The results demonstrated that PVPVA and HPMC improved and maintained the supersaturation of ketoconazole. PVPVA exhibited superior precipitation inhibitory effect on ketoconazole molecule aggregation due to slightly stronger van der Waals forces as well as unique electrostatic forces, thereby further enhancing in vitro drug absorption, which correlated well with in vivo drug absorption. Compared with a conventional dissolution apparatus paddle method, the DGIM improved the mean prediction error through the IVIVC from 19.30% to 9.96%, reaching the qualification criteria. In conclusion, the physiologically based multi-cup dissolution approach enables improved evaluation of supersaturation in gastrointestinal transportation of BCS IIB drug ketoconazole, enabling screening screen precipitation inhibitors and achieving qualified IVIVC for drug formulation studies.

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Section: Ivivcmentioning

confidence: 99%

Revisiting Supersaturation of a Biopharmaceutical Classification System IIB Drug: Evaluation via a Multi-Cup Dissolution Approach and Molecular Dynamic Simulation

Gan,

Xu,

Zhang

et al. 2023

Molecules

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“…"Fast crystallizers," however, can start to crystallize upon contact with an aqueous phase, or in some cases, even in environments of slightly increased humidity. An alternative approach to the shake flask method is the solvent shift method, where a supersaturated solution is created by dissolving the crystalline drug in an organic solvent such as methanol, DMSO, or THF (31). The drug/organic solvent mixture is subsequently added to the aqueous medium and precipitation is monitored via UV spectroscopy (Fig.…”

Section: Kinetic Solubility and Supersaturationmentioning

confidence: 99%

“…Compared to thermodynamic solubility measurements, determining the kinetic solubility is even more prone to inconsistencies. If this is an issue, both approaches along with different experimental setups (e.g., pH shift) should be investigated when possible (31).…”

Section: Kinetic Solubility and Supersaturationmentioning

confidence: 99%

“…Unfortunately, even with standardized protocols, precipitation is highly unpredictable and lacked repeatability. However, this approach may be used to rank formulations qualitatively (31) by evaluating how long a solution can stay supersaturated before precipitation occurs as a function of varying concentrations. Additionally, these solvent and pH shift methods can be used to investigate the effectiveness of various polymers in the formulation in helping maintain the supersaturated state (35) making them a valuable tool in formulation development.…”

Section: Precipitation and Dissolution Evaluation Of Asd Formulations...mentioning

confidence: 99%

“…Various dissolution approaches are commonly used during drug development to examine the performance of ASD formulations (1,6). During drug development, dissolution tests are often performed under pre-defined "bio-relevant" conditions by dissolving the dosage form in a single dissolution medium, often physiologically relevant one (i.e., Simulated Gastric fluid (SGF) or Fasted State Intestinal Fluid (FaSSIF)) or a combination of both in a 2-stage dissolution experiment aiming for simulating the gastrointestinal transfer of the drug/drug product (30,31). Measurements using media such as FaSSIF may be helpful to assess the effect of bile salts on the ASD formulation (38).…”

Section: Precipitation and Dissolution Evaluation Of Asd Formulations...mentioning

confidence: 99%

See 2 more Smart Citations

Challenges and Strategies for Solubility Measurements and Dissolution Method Development for Amorphous Solid Dispersion Formulations

Hermans

Milsmann

et al. 2022

AAPS J

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This manuscript represents the view of the Dissolution Working Group of the IQ Consortium on the challenges of and recommendations on solubility measurements and development of dissolution methods for immediate release (IR) solid oral dosage forms formulated with amorphous solid dispersions. Nowadays, numerous compounds populate the industrial pipeline as promising drug candidates yet suffer from low aqueous solubility. In the oral drug product development process, solubility along with permeability is a key determinant to assure sufficient drug absorption along the intestinal tract. Formulating the drug candidate as an amorphous solid dispersion (ASD) is one potential option to address this issue. These formulations demonstrate the rapid onset of drug dissolution and can achieve supersaturated concentrations, which poses significant challenges to appropriately characterize solubility and develop quality control dissolution methods. This review strives to categorize the different dissolution and solubility challenges for ASD associated with 3 different topics: (i) definition of solubility and sink conditions for ASD dissolution, (ii) applications and development of non-sink dissolution (according to conventional definition) for ASD formulation screening and QC method development, and (iii) the advantages and disadvantages of using dissolution in detecting crystallinity in ASD formulations. Related to these challenges, successful examples of dissolution experiments in the context of control strategies are shared and may lead as an example for scientific consensus concerning dissolution testing of ASD.

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Discovery solubility measurement and assessment of small molecules with drug development in mind

Barrett

Yang

Skolnik³

et al. 2022

Drug Discovery Today

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Comparison of induction methods for supersaturation: pH shift versus solvent shift

Cited by 7 publications

References 34 publications

Revisiting Supersaturation of a Biopharmaceutical Classification System IIB Drug: Evaluation via a Multi-Cup Dissolution Approach and Molecular Dynamic Simulation

Revisiting Supersaturation of a Biopharmaceutical Classification System IIB Drug: Evaluation via a Multi-Cup Dissolution Approach and Molecular Dynamic Simulation

Challenges and Strategies for Solubility Measurements and Dissolution Method Development for Amorphous Solid Dispersion Formulations

Discovery solubility measurement and assessment of small molecules with drug development in mind

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