Evaluation of Accuracy of Amorphous Solubility Advantage Calculation by Comparison with Experimental Solubility Measurement in Buffer and Biorelevant Media

Zhang, Wei; Haser, Abbe; Hou, Hao; Nagapudi, Karthik

doi:10.1021/acs.molpharmaceut.8b00125

Cited by 16 publications

(39 citation statements)

References 40 publications

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“…Solubility of amorphous IMC was measured in the same buffer used for intrinsic dissolution measurement by directly dissolving amorphous IMC in the buffer at 37 °C . The amorphous IMC was prepared by the melt quenching method as mentioned above.…”

Section: Methodsmentioning

confidence: 99%

Effect of Counterions on Dissolution of Amorphous Solid Dispersions Studied by Surface Area Normalized Dissolution

Chen¹,

Lubach²,

Tang³

et al. 2021

Mol. Pharmaceutics

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Solubility enhancement has become a common requirement for formulation development to deliver poorly water soluble drugs. Amorphous solid dispersions (ASDs) and salt formation have been two successful strategies, yet there are opportunities for further development. For ASDs, drug–polymer phase separation may occur at high drug loadings during dissolution, limiting the increase of drug loadings in ASD formulations. For salt formation, a salt form with high crystallinity and sufficient solid-state stability is required for solid dosage form development. This work studied the effect of counterions on the dissolution performance of ASDs. Surface area normalized dissolution or intrinsic dissolution methodology was employed to eliminate the effect of particle size and provide a quantitative comparison of the counterion effect on the intrinsic dissolution rate. Using indomethacin (IMC)–poly(vinylpyrrolidone-co-vinyl acetate) ASD as a model system, the effect of different bases incorporated into the ASD during preparation, the molar ratios between the base and IMC, and the drug loadings in the ASD were systematically studied. Strong bases capable of ionizing IMC significantly enhanced drug dissolution, while a weak base did not. A physical mixture of a strong base and the ASD also enhanced the dissolution rate, but the effect was less pronounced. At different base to IMC molar ratios, dissolution enhancement increased with the base to IMC ratio. At different drug loadings, without a base, the IMC dissolution rate decreased with the increase of drug loading. After incorporating a strong base, it increased with the increase of drug loading. The observations from this study were thought to be related to both the ionization of IMC in ASDs and the increase of microenvironment pH by the incorporated bases. With the significant enhancement of the drug dissolution rate, our work provides a promising approach of overcoming the dissolution limitation of ASD formulations at high drug loadings.

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Section: Methodsmentioning

confidence: 99%

Effect of Counterions on Dissolution of Amorphous Solid Dispersions Studied by Surface Area Normalized Dissolution

Chen¹,

Lubach²,

Tang³

et al. 2021

Mol. Pharmaceutics

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show abstract

“…Several dozen products using solid dispersion techniques are now commercially available. 7) As poorly water-soluble drug candidates become more common, the use of solid dispersion will increase.…”

Section: Introductionmentioning

confidence: 99%

Intermolecular Interactions between Drugs and Aminoalkyl Methacrylate Copolymer in Solution to Enhance the Concentration of Poorly Water-Soluble Drugs

Higashi

Ueda

Moribe

2019

CHEMICAL & PHARMACEUTICAL BULLETIN

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An aminoalkyl methacrylate copolymer, Eudragit ® E (EUD-E), has gained tremendous attention as a solid dispersion carrier because it efficiently stabilizes drugs in the amorphous state. Furthermore, EUD-E remarkably enhances drug dissolution in water. This review focuses on the interaction between drugs and EUD-E in solution, which contributes to the enhancement of drug concentration. Studies examining interactions between acidic drugs and EUD-E in organic solvents have revealed that the interaction occurs predominantly by electrostatic interaction, including hydrogen bonding and dipolar interactions. Other studies on interactions in aqueous solution found evidence for strong electrostatic interactions between acidic drugs and EUD-E in ion exchange experiments. 1 H-NMR studies using high-resolution magic-angle spinning, nuclear Overhauser effect spectroscopy, diffusion, and relaxation time measurements successfully identified the interaction site and strength in aqueous solution. Hydrophobic and ionic interactions occurred between drugs and EUD-E. The conformation of EUD-E, which was affected by the ionic strength and pH of the aqueous media, also influenced the interaction. The knowledge discussed in this review will be helpful in designing solid dispersion formulations with EUD-E, which will efficiently enhance drug concentration and subsequent absorption into the body.

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“…In the literature, the free base solubility of amorphous ritonavir is reported with values ranging from 27 μg/mL to 40 μg/mL. 15,16,20 A sensitivity analysis was performed on this parameter and it was found that the solubility of amorphous ritonavir between 35 and 40 μg/mL gave the simulated pharmacokinetic parameters AUC 0-t , C max , and T max in the range that was clinically observed. Thus, a value of 38.5 μg/mL was used as the free base aqueous solubility of amorphous ritonavir (Xu et al and Zhang et al 15,20 ).…”

Section: Methodsmentioning

confidence: 99%

“…15,16,20 A sensitivity analysis was performed on this parameter and it was found that the solubility of amorphous ritonavir between 35 and 40 μg/mL gave the simulated pharmacokinetic parameters AUC 0-t , C max , and T max in the range that was clinically observed. Thus, a value of 38.5 μg/mL was used as the free base aqueous solubility of amorphous ritonavir (Xu et al and Zhang et al 15,20 ). In addition, Law et al reported the solubility of amorphous ritonavir as 4 mg/mL in 0.1N HCL.…”

Section: Methodsmentioning

confidence: 99%

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Biopharmaceutic In Vitro In Vivo Extrapolation (IVIV_E) Informed Physiologically-Based Pharmacokinetic Model of Ritonavir Norvir Tablet Absorption in Humans Under Fasted and Fed State Conditions

et al. 2020

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Ritonavir is a well-known CYP3A4 and CYP2D6 enzyme inhibitor, frequently used to assess the drug–drug interaction (DDI) liability of susceptible drugs. It is also used as a pharmacokinetic booster to increase exposure to CYP3A4 substrates. This study aimed to develop a mechanistic absorption and disposition model to describe exposure to ritonavir following oral dosing of the commercial amorphous solid dispersion tablet, Norvir, under fasted and fed conditions. A mechanistic description of ritonavir absorption from Norvir tablets may help to improve the design of DDI studies. Key parameters of amorphous ritonavir including free base solubility (solubility of the unbound, un-ionized species), bile micelle partition coefficients, formulation wetting/disintegration, and in vivo precipitation parameters were either obtained from the literature or estimated by modeling in vitro biopharmaceutic experiments. Based on variety of in vitro evidence, a main assumption of the model is that ritonavir does not form a crystalline precipitate while resident in the gastrointestinal tract. In the model, if simulated luminal concentration exceeds the amorphous solubility limit, then precipitation to an amorphous form is immediate. Simulated and observed C max and AUC0‑t parameters were well captured (within 1.5-fold) for both fasted and fed states in healthy volunteers. By accounting for luminal fluid viscosity differences in the different prandial states (affecting drug diffusivity) as well as the effect of drug free fraction on gut wall permeation rates, it was possible to explain the negative food effect observed for Norvir tablets in humans. In summary, a biopharmaceutic in vitro in vivo extrapolation approach provides confidence in (verification of) key input parameters of the physiologically-based pharmacokinetic ritonavir model which resulted in successful simulation of observed plasma profiles.

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Evaluation of Accuracy of Amorphous Solubility Advantage Calculation by Comparison with Experimental Solubility Measurement in Buffer and Biorelevant Media

Cited by 16 publications

References 40 publications

Effect of Counterions on Dissolution of Amorphous Solid Dispersions Studied by Surface Area Normalized Dissolution

Effect of Counterions on Dissolution of Amorphous Solid Dispersions Studied by Surface Area Normalized Dissolution

Intermolecular Interactions between Drugs and Aminoalkyl Methacrylate Copolymer in Solution to Enhance the Concentration of Poorly Water-Soluble Drugs

Biopharmaceutic In Vitro In Vivo Extrapolation (IVIV_E) Informed Physiologically-Based Pharmacokinetic Model of Ritonavir Norvir Tablet Absorption in Humans Under Fasted and Fed State Conditions

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