Interaction and Compatibility Studies in the Development of Olmesartan Medoxomil and Hydrochlorothiazide Formulations under a Real Manufacturing Process

Murillo-Fernández, Mac Arturo; Montero-Zeledón, Ernesto; Abdala-Saiz, Ariadna; Vega-Baudrit, José Roberto; Araya-Sibaja, Andrea Mariela

doi:10.3390/pharmaceutics14020424

Cited by 4 publications

(3 citation statements)

References 42 publications

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“…PXRD was used as a technique to monitor the excipient compatibility of API [ 27 , 31 , 32 ]. The initial PXRD fingerprints obtained from the study samples were used as a baseline to monitor if changes in the formulation would be detectable through changes in their diffractograms.…”

Section: Discussionmentioning

confidence: 99%

“…A similar study used PXRD and other isothermal techniques to establish compatibility between propafenone HCl and lactose monohydrate [ 29 ]. Further studies reported PXRD as one of the spectroscopic methods for conducting API using excipient assessments to support the stability data for pharmaceutical products [ 30 , 31 , 32 ]. As there is evidence to support using PXRD to monitor formulation changes in pharmaceutical development, this study employed the technique as a tool to possibly detect changes in the diffractograms of the L-T 4 formulations used in the stability studies.…”

Section: Introductionmentioning

confidence: 99%

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Potency and Powder X-ray Diffraction (PXRD) Evaluation of Levothyroxine Sodium Tablets under Ambient, Accelerated, and Stressed Conditions

Okezue,

Byrn,

Probost

et al. 2023

Pharmaceuticals

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Levothyroxine tablets, although highly prescribed in the United States, have been one of the most frequently recalled products. Because of the importance of the medication, several efforts have been put in place by the United States Food and Drug Administration (US FDA) to control the quality of levothyroxine tablets available to patients using the drug. The choice of excipients used in the formulation has been shown to impact the hygroscopicity and microenvironment, and ultimately the stability of the levothyroxine tablets formulations. Based on information generated from the US FDA Enforcement Report database, one of the main reasons for recalls is the low potency of different batches of the product. The yearly product recall trends for levothyroxine formulations were determined using the FDA Enforcement Report database. Three brands of levothyroxine tablets were selected with excipient lists similar to those products that have been historically recalled. The samples were placed at ambient (~23 °C), accelerated stability (40 °C/75% RH), and stress (50 °C/75% RH) conditions for up to 6 months. Sample potencies were determined at 0, 1.5, 3, and 6 months using the methods for assay and impurities in the United States Pharmacopeia (USP) monograph for levothyroxine tablets. Additional sample monitoring was conducted by overlaying the initial powder X-ray diffractograms (PXRD) of the samples from 0 months with the patterns generated thereafter. There has been a decline in the number of levothyroxine tablets recalled over the years. The highest numbers of recalls were recorded in the years 2013 [33] and 2020 [23]; no recalls occurred in the years 2019 and 2022. All of the brands evaluated met the USP 95.0–105.0% assay requirements at 1.5 months under accelerated conditions; only one of the brands complied at 3 months. Under ambient conditions, two brands were stable at 6 months, with borderline assay results. For stability, levothyroxine was found in microgram quantities in the formulations and PXRD could not detect changes at these low levels. However, we found some distinguishing data for samples under stress conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Potency and Powder X-ray Diffraction (PXRD) Evaluation of Levothyroxine Sodium Tablets under Ambient, Accelerated, and Stressed Conditions

Okezue,

Byrn,

Probost

et al. 2023

Pharmaceuticals

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“…[ 22 ] However, there are many published articles concerning its incompatibility with pharmaceutical ingredients due to its hydrophobic nature, the presence of the positively charged magnesium ion, and its strong surface energetic behavior. [ 23 24 25 ] Gelucire 48/16 is a member of the Gelucire family, is a mixture of mono, di, and triglycerides with PEG esters of fatty acids, working as nonionic surfactants and used in lipid-based formulations to increase solubility and bioavailability of poorly soluble drugs. [ 26 ] However, there is a lack of research data regarding their compatibility behavior toward drugs.…”

Section: Introductionmentioning

confidence: 99%

Modafinil-excipient compatibility study using differential scanning calorimetry

Omari

Sallam²,

Al-Hmoud³

et al. 2023

J Adv Pharm Technol Res

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Drug excipient compatibility studies are considered important in successful formulation of drug products. Suggested methods for this purpose are thermal techniques under isothermal or nonisothermal conditions. In this study, modafinil, a wakefulness-promoting drug, was investigated under nonisothermal conditions using differential scanning calorimetry. Four different heating rates, 5, 10, 15, and 20°C/min, were performed for modafinil pure material and its physical mixtures with magnesium stearate (MgSt) or Gelucire 48/16. Activation energy (Ea) was calculated from the straight line of plotting a function of heating rate versus temperature and found that modafinil-Gelucire physical mixture increased Ea. This indicates drug-excipient interaction, supported by evidence from Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. No significant interaction was detected with MgSt.

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A comprehensive compatibility study of ganciclovir with some common excipients

Mishra,

Sinha,

Sharma

et al. 2023

AJBPS

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Objectives: The aim of the present study is to illustrate compatibility testing of ganciclovir (GCV) with some common excipients that would be used to manufacture solid oral dosage forms. Different spectroscopy techniques were utilized to see the interaction of GCV with excipients such as lactose, microcrystalline cellulose (MCC), magnesium stearate, and talc, and dicalcium phosphate. Further, a molecular docking study was also done to know the interaction of GCV with excipients. In vitro study of a physical mixture of GCV with excipients was performed to get the release of drug. Material and Methods: A number of analytical techniques (differential scanning calorimetry [DSC] using DSC-Q20, TA instruments, Fourier-transform infrared spectroscopy [FTIR] spectroscopy using Spectrum RX 1, nuclear magnetic resonance [NMR] using Bruker Advance Neo 500 MHz NMR spectrometer, etc.) have been used to explore the drug-excipient compatibility. Further, a suspected interaction was evaluated by thin-layer chromatography (TLC). In vitro dissolution studies in different sets of experiments were accomplished to determine the influence of hydrophobic and hydrophilic attributes of excipients (MCC, lactose, dicalcium phosphate, and talc) on the dissolution profile of GCV using USP1-type dissolution apparatus. Furthermore, in silico molecular docking studies were also performed to evaluate any probable molecular interactions among drugs and excipients using Auto Dock VINA 1.2.0 software and GROMACS 5.0 software. Results: Comparing FTIR and 1H NMR spectra of GCV and physical mixtures of GCV and excipients, no significant deviation of characteristic peaks in infrared spectroscopy and 1H NMR signals was observed. The DSC of GCV showed two sharp endothermic peaks at 238.82°C and 255°C. The endothermic peak of GCV in DSC thermogram of physical mixtures was observed in nearly the same position except with lactose and dicalcium phosphate. A slightly deviated peak of GCV with a physical mixture of drug and lactose and dicalcium phosphate indicated that there were suspected interactions between the drug with lactose and dicalcium phosphate. These interactions were evaluated by thin-layer chromatography (TLC) and it confirmed that there was no interaction between drugs and excipients. In vitro dissolution studies determined the influence of hydrophobic and hydrophilic attributes of excipients on the dissolution profile of GCV. The physical mixture of GCV with MCC displayed a maximum amount (66.48%) of drug release in 10 min. On the other hand, a physical mixture of GCV with talc showed a minimum amount (12.08%) of drug release in 10 min. Docking study predicted that the number of interactions were more between GCV and lactose (four nos.) in comparison to GCV and MCC (two nos.). This interaction supported the in vitro drug release of a physical mixture of GCV with MCC which was higher than a mixture of GCV with lactose. Conclusion: Compatibility testing of GCV with used excipients by analytical techniques confirmed that GCV should be compatible with used excipients. Drug dissolution of GCV and physical mixture of MCC exhibited the maximum amount of drug release whereas a mixture of GCV with talc released the minimum amount of drug for both short (10 min.) and long (60 min.) periods. Docking studies disclosed that the lactose complex showed less deviation with less root mean square deviation value in comparison to the microcrystalline complex. Thus, the lactose complex has more hydrogen bonds and it was more stable as compared with the MCC complex. GCV indicates that the total energy of the MCC complex is less than that of the lactose complex. This indicates that GCV is more soluble when combined with the microcrystalline complex. Therefore, GCV and used excipients could be used for solid dosage formulations.

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Interaction and Compatibility Studies in the Development of Olmesartan Medoxomil and Hydrochlorothiazide Formulations under a Real Manufacturing Process

Cited by 4 publications

References 42 publications

Potency and Powder X-ray Diffraction (PXRD) Evaluation of Levothyroxine Sodium Tablets under Ambient, Accelerated, and Stressed Conditions

Potency and Powder X-ray Diffraction (PXRD) Evaluation of Levothyroxine Sodium Tablets under Ambient, Accelerated, and Stressed Conditions

Modafinil-excipient compatibility study using differential scanning calorimetry

A comprehensive compatibility study of ganciclovir with some common excipients

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