Influence of the Efavirenz Micronization on Tableting and Dissolution

Pinto, Enrico; Carmo, Flávia Almada do; Honorio, Thiago da Silva; Barros, Rita de Cássia da Silva Ascenção; Castro, Helena C.; Rodrigues, Carlos Rangel; Esteves, Valéria Sant Anna Dantas; Rocha, Helvécio Vinícius Antunes; Sousa, Valéria Pereira de; Cabral, Lúcio Mendes

doi:10.3390/pharmaceutics4030430

Cited by 9 publications

(8 citation statements)

References 16 publications

(23 reference statements)

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“…The thermal behavior of active pharmaceutical ingredients (APIs) as pure components in binary mixtures with excipients and in pharmaceutical formulations is of great importance in drug science [21][22][23][24][25][26]. Even if in the case of pharmaceuticals, the term "stability" is usually correlated with the loss of the active pharmaceutical ingredient from formulation, and "solid-state stability" can also designate the response of an API or a pharmaceutical formulation to thermal stress.…”

Section: Introductionmentioning

confidence: 99%

Solid State Stability and Kinetics of Degradation for Candesartan—Pure Compound and Pharmaceutical Formulation

et al. 2020

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The aim of this work was to assess the impact of an excipient in a pharmaceutical formulation containing candesartan cilexetil over the decomposition of the active pharmaceutical ingredient and to comparatively investigate the kinetics of degradation during thermolysis in an oxidative atmosphere under controlled thermal stress. To achieve this, the samples were chosen as follows: pure candesartan cilexetil and a commercial tablet of 32 mg strength. As a first investigational tool, Universal attenuated total reflection Fourier transform infrared (UATR-FTIR) spectroscopy was chosen in order to confirm the purity and identity of the samples, as well as to check if any interactions took place in the tablet between candesartan cilexetil and excipients under ambient conditions. Later on, samples were investigated by thermal analysis, and the elucidation of the decomposition mechanism was achieved solely after performing an in-depth kinetic study, namely the use of the modified non-parametric kinetics (NPK) method, since other kinetic methods (American Society for Testing and Materials—ASTM E698, Friedman and Flynn–Wall–Ozawa) led to inadvertencies. The NPK method suggested that candesartan cilexetil and the tablet were degraded by the contribution of two steps, the main being represented by chemical degradation and the secondary being a physical transformation. The excipients chosen in the formulation seemed to have a stabilizing effect on the decomposition of the candesartan cilexetil that was incorporated into the tablet, relative to pure active pharmaceutical ingredient (API), since the apparent activation energy for the decomposition of the tablet was 192.5 kJ/mol, in comparison to 154.5 kJ/mol for the pure API.

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Section: Introductionmentioning

confidence: 99%

Solid State Stability and Kinetics of Degradation for Candesartan—Pure Compound and Pharmaceutical Formulation

et al. 2020

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“…The physical, biopharmaceutical and pharmacokinetic properties of three batches of EFV API were systematically investigated. For the so-called brick dust drugs, such as EFV, this is a crucial step during the development of a generic solid oral dosage form [18,19].…”

Section: Discussionmentioning

confidence: 99%

“…Although distinct polymorphs of EFV have been reported [41], the most stable polymorph I present a melting range of 138 C -140 C and pattern peaks of X-ray diffraction of 6.3 ± 0.02 , 14.1 ± 0.02 , 16.8 ± 0.02 , and 24.8 ± 0.02 at 2h [9,11,19,22,42]. By comparing these data with the findings obtained in our study (Figure 2), it is possible to surmise that all batches of EFV investigated herein were composed of polymorph I.…”

Section: Discussionmentioning

confidence: 99%

“…Most of the studies investigating the intrinsic dissolution of EFV used the USP 2 paddle apparatus set at 50 rpm and 300-900 mL of aqueous dissolution medium containing SLS (0.25% 2.0%, w/v), Tween 80 (0.1%, w/v), and even a mixture of water/methanol (60:40, v/v) [3,9,[14][15][16][17][18][19]. These dissolution media may not be able to distinguish the dissolution rates of the API.…”

Section: Introductionmentioning

confidence: 99%

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Characterization, in vitro dissolution, and pharmacokinetics of different batches of efavirenz raw materials

Bedor

Neto

et al. 2021

Drug Development and Industrial Pharmacy

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Objective: To perform the solid-state characterization and the in vitro-in vivo correlation (IVIVC) of three batches of efavirenz (EFV) active pharmaceutical ingredients. Significance: EFV is an effective anti-HIV drug. Due to the poor aqueous solubility, the rate and extent of EFV absorption deeply depend on its dissolution characteristics. Methods: Thermal analyses, x-ray diffraction, and particle size distribution were performed. The saturation solubility and dissolution profiles were assessed in 0.5% (w/v) sodium lauryl sulfate (SLS), fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF) using a flow-through cell. Each batch was orally administered to Wistar rats and the pharmacokinetic parameters were correlated with those obtained from in vitro dissolution. Results: All batches of EFV consisted polymorph I. EFV-A presented the lowest particle size distribution [d(v,0.5) ¼ 197.8 mm; d(v,0.9) ¼ 444.6 mm] followed by EFV-B [d(v,0.5) ¼ 223.9 mm; d(v,0.9) ¼ 481.1 mm], and EFV-C [d(v,0.5) ¼ 240.8 mm; d(v,0.9) ¼ 497.3 mm]. The saturated solubility in FaSSIF was 36% and 40% of that in FeSSIF and SLS, respectively. EFV-A presented the fastest rate and largest extension of dissolution than EFV-B and C (79.15%, 69.93% and 54.22%, respectively, as well as the highest maximum plasma concentration. Levels B, C, and multiple-C of IVIVC models were achieved. Conclusion:The FaSSIF medium discriminated the dissolution profiles of EFV APIs. Small differences in particle size distribution had a significant impact on the biopharmaceutical parameters of EFV, suggesting that strict control of such parameter is an important aspect during API development and drug formulation.

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“…Solubility studies of EFV have been well-established in regular dissolution media (USP requirement monograph), and several discriminative dissolution methods have been developed (37,54,55). However, solubility studies of different polymorphic forms of EFV in a comparative in vitro medium have not been reported.…”

Section: Saturation In Vitro Solubility Studiesmentioning

confidence: 99%

In Vitro Solubility and Release Profile Correlation with pKa Value of Efavirenz Polymorphs

Wardhana¹,

Aisyah²,

Sopyan³

et al. 2021

Dissolution Technol.

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Efavirenz (EFV) was approved by the United States Food and Drug Administration in 1998 with no polymorphic forms, but further research defined 23 different forms, including amorphous and solvated forms. This study aims to determine the ability of dissolved EFV polymorphs in in vitro media kinetic release models of pKa values. The polymorph types were obtained through various organic solvents such as acetonitrile, n-hexane, and methanol, i.e., form I, II, and III. The characteristics were distinguished by polarisation microscopy, differential scanning calorimetry (DSC), Fourier transform infrared (FTIR), and Raman spectroscopy. The solubility and dissolution of each polymorph were examined by adding 0.25% sodium lauryl sulphate (SLS) to the comparative dissolution media (water, HCl at pH 1.2, phosphate buffer at pH 4.6 and 6.8). The different microscopic shapes provided a unique fingerprint in the FTIR and the Raman spectra. The thermal behaviour examination provided a DSC thermogram with a specific melting point for each polymorph. The results of the solubility and dissolution tests reported that the highest peak was reached by form II, followed by forms III and I. These followed the pKa values of each polymorph, namely 10.12, 10.63, and 10.37 for form I, II, and III, respectively. The dissolution profile shows that pH conditions affect the release kinetics of form I compared to the metastable forms. The kinetic model of form I is pH-dependent; the acidic medium provided a slower release rate. Unlike the metastable forms, drug loading remained constant but still followed Higuchi's kinetic release model, even in acidic medium.

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Influence of the Efavirenz Micronization on Tableting and Dissolution

Cited by 9 publications

References 16 publications

Solid State Stability and Kinetics of Degradation for Candesartan—Pure Compound and Pharmaceutical Formulation

Solid State Stability and Kinetics of Degradation for Candesartan—Pure Compound and Pharmaceutical Formulation

Characterization, in vitro dissolution, and pharmacokinetics of different batches of efavirenz raw materials

In Vitro Solubility and Release Profile Correlation with pKa Value of Efavirenz Polymorphs

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