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1.
Rapid Commun Mass Spectrom ; 38(11): e9745, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38591150

RESUMO

RATIONALE: As per International Council for Harmonization (ICH) drug stability test guideline Q1A(R2), inherent stability characteristics of a drug should be studied. This work was designed to investigate inherent degradation characteristics of the drug idelalisib under ICH prescribed stress conditions, identify its degradation products, and postulate their corresponding degradation pathways. METHODS: Idelalisib was subjected to the ICH prescribed conditions of hydrolytic (neutral, acidic, and alkaline), photolytic, oxidative, and thermal stress according to ICH guideline Q1A(R2). An ultrahigh-performance liquid chromatography with photodiode array (UHPLC-PDA) method was developed to adequately resolve the drug from its degradation products, validated as per the ICH guidelines, and subsequently extended to UHPLC with electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-QTOFMS) studies to identify the degradation products. RESULTS: Significant degradation was noted under conditions of acidic/alkaline hydrolysis, acid photolysis, and oxidative stress. The UHPLC/ESI-QTOFMS studies revealed the generation of four degradation products (I-IV), which were satisfactorily resolved from the drug by UHPLC on a Kinetex® C18 (100 × 4.6 mm; 2.6 µm) column by the developed isocratic elution method. Detection wavelength was selected as 270 nm. All the degradation products (I-IV) could be identified and characterized from their mass spectral data. The degradation pathways for the generation of various products from the drug were postulated. CONCLUSIONS: A UHPLC-PDA method was developed and validated for idelalisib. Four degradation products of idelalisib were revealed through UHPLC/ESI-QTOFMS studies, and corresponding degradation pathways were postulated for the same.


Assuntos
Purinas , Quinazolinonas , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida/métodos , Hidrólise , Estabilidade de Medicamentos , Oxirredução , Fotólise , Cromatografia Líquida de Alta Pressão/métodos
2.
AAPS J ; 26(3): 40, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570383

RESUMO

In a lyophilized protein/disaccharide system, the ability of the disaccharide to form a homogeneous mixture with the protein and to slow the protein mobility dictates the stabilization potential of the formulation. Human serum albumin was lyophilized with sucrose or trehalose in histidine, phosphate, or citrate buffer. 1H T1 relaxation times were measured by solid-state NMR spectroscopy and were used to assess the homogeneity and mobility of the samples after zero, six, and twelve months at different temperatures. The mobility of the samples decreased after 6 and 12 months storage at elevated temperatures, consistent with structural relaxation of the amorphous disaccharide matrix. Formulations with sucrose had lower mobility and greater stability than formulations with trehalose.


Assuntos
Sacarose , Trealose , Humanos , Trealose/química , Temperatura , Albumina Sérica Humana , Estabilidade de Medicamentos , Dissacarídeos , Espectroscopia de Ressonância Magnética , Liofilização
3.
Int J Mol Sci ; 25(5)2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38473837

RESUMO

As part of the development and production of pharmaceuticals, the purity of Active Pharmaceutical Ingredients stands as a fundamental parameter that significantly influences the quality, safety, and efficacy of the final drug product. Impurities in Active Pharmaceutical Ingredients are various unwanted substances that can appear during the whole manufacturing process, from raw materials to the final product. These impurities can stem from multiple sources, including starting materials, intermediates, reagents, solvents, and even degradation products resulting from exposure to environmental factors such as heat, light, or moisture. Their presence can potentially compromise the therapeutic effect of the drug, introduce unexpected side effects, or even pose safety risks to patients. This study aims to conduct the forced degradation of linagliptin and subsequently attempt to identify the resulting degradants. The degradation procedures were carried out in accordance with the guidelines of the International Committee for Harmonization. The degradation profile of linagliptin was investigated under various conditions, including acid hydrolysis, alkaline hydrolysis, oxidation, heat, and light exposure, utilizing ultra-performance liquid chromatography connected to a photo array detector. Identification and characterization of the degradation products were achieved using an ultra-performance liquid chromatography coupled with a single quadrupole detector mass spectrometer and also a liquid chromatography coupled with a high-resolution mass spectrometry. The identified degradation products demonstrate that linagliptin is particularly susceptible to degradation when exposed to acid and peroxide. Whereas, no significant degradation effects were observed under alkali, thermolytic, and photolytic conditions.


Assuntos
Linagliptina , Humanos , Espectrometria de Massas , Cromatografia Líquida/métodos , Oxirredução , Hidrólise , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos
4.
Int J Pharm ; 654: 123991, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38471578

RESUMO

The degradation of peptide drugs limits the application of peptide drug microspheres. Structural changes of peptides at the water-oil interface and the destruction of their spatial structure in the complex microenvironment during polymer degradation can affect drug release and in vivo biological activity. This study demonstrates that adding hydroxyethyl starch (HES) to the internal aqueous phase (W1) significantly enhances the stability of semaglutide and optimizes its release behavior in PLGA microspheres. The results showed that this improvement was due to a spontaneous exothermic reaction (ΔH = -132.20 kJ mol-1) facilitated by hydrogen bonds. Incorporating HES into the internal aqueous phase using the water-in-oil-in-water (W1/O/W2) emulsion method yielded PLGA microspheres with a high encapsulation rate of 94.38 %. Moreover, microspheres with HES demonstrated well-controlled drug release over 44 days, unlike the slower and incomplete release in microspheres without HES. The optimized h-MG2 formulation achieved a more complete drug release (83.23 %) and prevented 30.65 % of drug loss compared to the HES-free microspheres within the same period. Additionally, the optimized semaglutide microspheres provided nearly three weeks of glycemic control with adequate safety. In conclusion, adding HES to the internal aqueous phase improved the in-situ drug stability and release behavior of semaglutide-loaded PLGA microspheres, effectively increasing the peptide drug payload in PLGA microspheres.


Assuntos
Peptídeos Semelhantes ao Glucagon , Ácido Láctico , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ácido Láctico/química , Ácido Poliglicólico/química , Estabilidade de Medicamentos , Microesferas , Composição de Medicamentos/métodos , Tamanho da Partícula , Peptídeos , Água , Amido/química
5.
J Pharm Biomed Anal ; 243: 116085, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38471254

RESUMO

Eltrombopag is an oral non-peptide thrombopoietin receptor (TPO-R) agonist indicated for the treatment of thrombocytopenia in patients with persistent or chronic immune thrombocytopenia (idiopathic thrombocytopenic purpura, ITP) or chronic hepatitis C infection and the treatment of severe aplastic anemia. The purpose of this research was to assess the possible impurities that may carry over to eltrombopag from its precursor Eltro-1 (3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid) and to develop a specific analytical method for the determination of these impurities. Eltro-1 samples synthesized by two different synthesis routes were investigated during the evaluation and method development studies. Besides the expected process-related impurities (Eltro-1A - Eltro-1J), e.g., starting materials, intermediates, and/or compounds formed from their further reactions, an unknown impurity detected above 0.10% was identified by LC-MS, synthesized and fully characterized by NMR, MS and FTIR (Eltro-1K). Accordingly, an HPLC-RP method for the determination of eleven impurities (Eltro-1A - Eltro-1K) in Eltro-1 was developed and validated according to ICH Q2. The control limits for impurities in Eltro-1 were set at ≤ 0.15% for Eltro-1A - Eltro-1J and ≤ 1.0% for Eltro-1K based on fate, spike-purge and carryover studies and in accordance with the ICH M7 classification for impurities in drug substance. Eltro-1 and eleven impurities at the specification limit were separated from each other and the diluent peaks with sufficient resolution without interference. Separation was performed on a Waters XBridge C18 column (150 × 4.6 mm, 3.5 µm) at 40 °C with a 10 µL injection volume at a detection wavelength of 220 nm and 15 °C sample temperature. The gradient elution is performed at a flow rate of 1.0 mL/min for 40 min with mobile phase A (0.1% orthophosphoric acid in water) and B (acetonitrile) according to the following program: Time (min) / Acetonitrile (%): 0/0, 35/70, 36/0, 40/0. Test and standard solutions were prepared at a concentration of 1.0 mg/mL and 1.0 µg/mL, respectively, using a mixture of mobile phase A and acetonitrile (75/25) as diluent. This is the first specific, selective, sensitive, linear, precise, accurate, and robust HPLC method for the determination of Eltro-1A - Eltro-1K in Eltro-1, which showed no significant degradation under thermal stress, photostability (UV and VIS), and standard accelerated and long-term stability conditions.


Assuntos
Benzoatos , Contaminação de Medicamentos , Hidrazinas , Pirazóis , Humanos , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Acetonitrilas , Reprodutibilidade dos Testes
6.
J Pharm Biomed Anal ; 243: 116117, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38522383

RESUMO

Ubrogepant is the first oral calcitonin gene-related peptide (CGRP) receptor antagonist which is used for the acute treatment of migraine in adults. The present study employs liquid chromatography-high resolution mass spectrometry (LC-HRMS) and nuclear magnetic resonance spectroscopy (NMR) techniques for the identification and characterization of degradation impurities of ubrogepant. The forced degradation study of ubrogepant was performed as per the International Council for Harmonisation (ICH) Q1A and Q1B guidelines. The in silico degradation profile of ubrogepant was predicted by Zeneth. It was observed that ubrogepant was labile to acidic hydrolysis, basic hydrolysis, and oxidative degradation conditions (H2O2), although it was stable in neutral hydrolysis and photolytic (UV light and visible light) conditions. Eight degradation impurities were formed, which were separated on reversed-phase HPLC with a gradient program on an InertSustain C8 column (4.6 × 250 mm, 5 µm) using 10 mM ammonium formate (pH unadjusted) and acetonitrile as the mobile phase. The structures of all the degradation impurities were characterized using the exact masses obtained from the HRMS/MS. Further, NMR studies were conducted on two major degradation impurities (UB-4 and UB-7). A plausible mechanism was proposed to support the structures of all the degradation impurities of UBR. In silico toxicity and mutagenicity assessment were done by DEREK Nexus, SARAH Nexus, and ProTox-II.


Assuntos
Peróxido de Hidrogênio , Piridinas , Pirróis , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos , Espectroscopia de Ressonância Magnética/métodos , Oxirredução , Hidrólise , Estabilidade de Medicamentos
7.
Mol Pharm ; 21(4): 1691-1704, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38430187

RESUMO

In the clinical application of freeze-dried highly concentrated omalizumab formulations, extensive visible bubbles (VBs) can be generated and remain for a long period of time in the reconstitution process, which greatly reduces the clinical use efficiency. It is necessary to understand the forming and breaking mechanism of VBs in the reconstitution process, which is a key factor for efficient and safe administration of biopharmaceutical injection. The effects of different thermal treatments on the volume of VBs and stability of omalizumab, mAb-1, and mAb-2 were investigated. The internal microvoids of the cake were characterized by scanning electron microscopy and mercury intrusion porosimetry. Electron paramagnetic resonance was applied to obtain the molecular mobility of the protein during annealing. A large number of VBs were generated in the reconstitution process of unannealed omalizumab and remained for a long period of time. When annealing steps were added, the volume of VBs was dramatically reduced. When annealed at an aggressive temperature (i.e., -6 °C), although the volume of VBs decreased, the aggregation and acidic species increased significantly. Thus, our observations highlight the importance of setting an additional annealing step with a suitable temperature, which contributes to reducing the VBs while maintaining the stability of the high concentration freeze-dried protein formulation.


Assuntos
Omalizumab , Proteínas , Temperatura , Liofilização , Estabilidade de Medicamentos
8.
Eur J Pharm Sci ; 195: 106722, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38336250

RESUMO

Posaconazole is a broad-spectrum antifungal agent exhibiting rich polymorphism. Up to now, a total of fourteen different crystal forms have been reported, sometimes with an ambiguous nomenclature, but less is known about their properties and stability relationships. Investigating the solid-state of a drug compound is essential to identify the most stable form under working conditions and to prevent the risk of undesired solid-phase transformations under processing and storage. In this paper, we study posaconazole polymorphism by providing a description of its polymorphs, hydrates, and solvates. Powder X-ray diffraction (PXRD), dynamic vapor sorption (DVS), spectroscopic and thermal techniques were employed to characterize the different forms. In addition, the solid-phase transformations of posaconazole in aqueous suspensions were studied by means of Raman microscopy. Surprisingly, we found that Form S, the crystal form contained in the marketed oral suspension, is not the most stable form in water. Form S readily converts to a more stable hydrate, i.e. Form A, after storage in water for two weeks. In the commercial oral formulation the conversion between the two forms is prevented by the presence of polysorbate 80. Such insights into the stabilizing excipient effects beyond particle dispersion are critical to formulators.


Assuntos
Triazóis , Água , Água/química , Cristalização/métodos , Estabilidade de Medicamentos , Difração de Raios X , Varredura Diferencial de Calorimetria
9.
Int J Pharm ; 654: 123938, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38408554

RESUMO

The stability of lactate dehydrogenase (LDH) and ß-galactosidase (ß-gal), incorporated in arginine/pullulan (A/P) mixtures at various weight ratios by lyophilization, was determined. The physicochemical characteristics of various A/P mixtures were assessed. With decreasing A/P ratios, the glass transition temperature of the formulations increased. Furthermore, arginine crystallization due to high relative humidity (RH) exposure was prevented at an A/P weight ratio of 4/6 or less. When stored at 0 % RH / 60 °C for 4 weeks, arginine was superior to pullulan as stabilizer. During storage at 43 % RH / 30 ℃ for 4 weeks, the enzymatic activity of LDH was best retained at an A/P weight ratio of 2/8, while ß-gal activity was relatively well-retained at A/P weight ratios of both 8/2 and 2/8. LDH seemed to be more prone to degradation in the rubbery state. In the glassy state, ß-gal degraded faster than LDH. Solid-state nuclear magnetic resonance spectroscopy showed that (labeled) arginine experienced a different interaction in the two protein samples, reflecting a modulation of long-range correlations of the arginine side chain nitrogen atoms (Nε, Nη). In summary, LDH stabilization in the A/P matrix requires vitrification. Further stabilization difference between LDH and ß-gal may be dependent on the interaction with arginine.


Assuntos
Arginina , Proteínas , Arginina/química , Proteínas/química , Glucanos , L-Lactato Desidrogenase/química , Liofilização/métodos , Estabilidade de Medicamentos
10.
Molecules ; 29(3)2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38338332

RESUMO

In total, three related substances (RS) associated with sotalol hydrochloride (STHCl) were herein identified with a novel gradient high-performance liquid chromatography (HPLC) protocol. Further characterization of these substances was then performed via liquid chromatography-mass spectroscopy (LC-MS/MS) and nuclear magnetic resonance (NMR) approaches. For these analyses, commercial STHCl samples were used for quantitative HPLC studies and the degradation of STHCl under acidic (1M HCl), alkaline (1M NaOH), oxidative (30% H2O2), photolytic (4500 Lx), and thermal stress conditions (100 °C) was assessed. This approach revealed this drug to be resistant to acidic, alkaline, and high-temperature conditions, whereas it was susceptible to light and oxidation as confirmed through long-term experiments. The putative mechanisms governing RS formation were also explored, revealing that RS3 was derived from the manufacturing process, whereas RS2 was generated via oxidation and RS1 was generated in response to light exposure. The cytotoxicity of these RS compounds was then assessed using MTT assays and acute toxicity test. Overall, this study provides details regarding the characterization, isolation, quantification, and toxicological evaluation of STHCl and associated RS compounds together with details regarding the precise, specific, and reliable novel HPLC technique, thus providing the requisite information necessary to ensure STHCl purity and safety.


Assuntos
Sotalol , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Sotalol/farmacologia , Espectrometria de Massas em Tandem/métodos , Peróxido de Hidrogênio , Estabilidade de Medicamentos , Hidrólise , Oxirredução , Fotólise
11.
Int J Pharm ; 653: 123868, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38309485

RESUMO

Extemporaneous preparation (EP) formulation is an attractive strategy to accelerate the formulation development of new chemical entities for first entry into human study. In this work, an EP suspension formulation for a development drug candidate GDC-6599 was successfully developed. The formulation spanned a wide concentration range from 0.1 to 2.0 mg/mL. A non-solubilizing vehicle, 0.6 % (w/v) methylcellulose solution was used to suspend GDC-6599. An aversive agent denatonium benzoate at an extremely low level (6 ppm) was applied as a taste masking agent. This enabled a simple matrix for the analysis of related substances from GDC-6599 during all stability studies. Microcrystalline cellulose at 10 mg/mL concentration was added to the EP formulation to generate a suspension appearance, leading to the success of using a single placebo for matching active formulation at all concentrations. The developed formulation demonstrated excellent homogeneity, sufficient stability and passed microbiological enumeration test. Rinsing performance test demonstrated that greater than 99.8 % amount of drug was successfully recovered by rinsing with water twice, providing guidance for clinical dosing. Biopharmaceutical assessment was conducted by both in silico simulation and in vitro tests. Greater than 90 % bioaccessibility of the EP suspension formulation was obtained via an in vitro system mimicking the human gastrointestinal absorption, consistent with the result from the in silico modeling. The developed EP formulation was successfully used to support the early single ascending dose (SAD) cohorts of GDC-6599 Phase I clinical study. The formulation matrix and assessment workflow developed in this work are generalizable as a platform for EP formulation development of new chemical entities for early phase clinical studies.


Assuntos
Celulose , Absorção Gastrointestinal , Humanos , Composição de Medicamentos , Administração Oral , Percepção Gustatória , Estabilidade de Medicamentos
12.
Artigo em Inglês | MEDLINE | ID: mdl-38423709

RESUMO

Regorafenib is a small molecule tyrosine kinase inhibitor administered orally drug, act by inhibiting the activity of the VEGF receptors. It is used for the treatment of patients with metastatic colorectal cancer (CRC), advanced gastrointestinal stromal tumors, and hepatocellular carcinoma. This comprehensive profile on regorafenib includes an original data as well as data collected from the literature on Profiles of Methods of Drug Synthesis, different Physical Drug Profiles, Drug Analytical methods and Pharmacological profile (ADME). This chapter is divided into five main sections: General Description of the drug, Physical Characteristics, Methods of Preparation, Methods of Analysis, Pharmacology and List of References. These main sections are further divided to many sub-titles to cover most aspect of the drug in the light of the available literature. Among these sub-titles are the formulae, Elemental Analysis, physical characteristics which include constant of ionization, solubility, X-ray powder diffraction pattern, TGA, thermal conduct and spectroscopic and stability. Additionally, analytical techniques including Electrochemical, Spectrophotometric and chromatographic methods, ADME profiles and pharmacological effects were also discussed. Furthermore, methods and schemes are outlined for the preparation of the drug substance.


Assuntos
Compostos de Fenilureia , Piridinas , Humanos , Estabilidade de Medicamentos , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico
13.
Int J Pharm ; 653: 123884, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38341049

RESUMO

Predicting drug-excipient compatibility is a critical aspect of pharmaceutical formulation design. In this study, we introduced an innovative approach that leverages machine learning techniques to improve the accuracy of drug-excipient compatibility predictions. Mol2vec and 2D molecular descriptors combined with the stacking technique were used to improve the performance of the model. This approach achieved a significant advancement in the predictive capacity as demonstrated by the accuracy, precision, recall, AUC, and MCC of 0.98, 0.87, 0.88, 0.93 and 0.86, respectively. Using the DE-INTERACT model as the benchmark, our stacking model could remarkably detect drug-excipient incompatibility in 10/12 tested cases, while DE-INTERACT managed to recognize only 3 out of 12 incompatibility cases in the validation experiments. To ensure user accessibility, the trained model was deployed to a user-friendly web platform (URL: https://decompatibility.streamlit.app/). This interactive interface accommodated inputs through various types, including names, PubChem CID, or SMILES strings. It promptly generated compatibility predictions alongside corresponding probability scores. However, the continual refinement of model performance is crucial before applying this model in practice.


Assuntos
Química Farmacêutica , Excipientes , Química Farmacêutica/métodos , Estabilidade de Medicamentos , Incompatibilidade de Medicamentos , Aprendizado de Máquina
14.
Rapid Commun Mass Spectrom ; 38(5): e9696, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38355880

RESUMO

RATIONALE: Enasidenib (EDB) is an orally active selective mutant isocitrate dehydrogenase-2 enzyme inhibitor approved by the U.S. Food and Drug Administration to treat acute myeloid leukemia. It lacks a reported forced degradation study and a stability-indicating assay method (SIAM). This study addresses this gap by establishing a degradation profile in accordance with the International Council for Harmonisation Q1A and Q1B (R2) guidelines and developing a validated SIAM for EDB. METHODS: EDB was exposed to forced degradation under various conditions (hydrolytic, photolytic, oxidative, and thermal stress). Degradation samples were analyzed using high-performance liquid chromatography on an Agilent ZORBAX Eclipse Plus C18 column with a mobile phase consisting of 0.1% formic acid in Milli-Q water and acetonitrile at a flow rate of 1 mL/min and detection at 270 nm. Liquid chromatography-quadrupole time-of-flight-high-resolution mass spectrometry (LC/Q-TOF HRMS) was used for the identification and characterization of degradation products. Nitrosamine risk assessment was conducted using a modified nitrosation assay procedure (NAP) test due to the presence of a secondary amine group in the drug, which is liable to forming nitrosamine drug substance-related impurities (NDSRI). RESULTS: The drug exhibited significant degradation under acidic, basic, photolytic, and oxidative conditions in the solution state. A total of nine degradation products (DP) were formed (DP-I, DP-III, and DP-IV: acidic conditions; DP-I and DP-III: basic conditions; DP-II, DP-V, DP-VI, and DP-VII: oxidative stress; and DP-VII, DP-VIII, and DP-IX: photolytic conditions), which were separated and identified using reversed-phase high-performance liquid chromatography and characterized using liquid chromatography-tandem mass spectrometry. The mechanism behind the formation of EDB degradation products has been discussed, and this study was the first to develop a degradation pathway for EDB. In addition, the possibilities of NDSRI formation for EDB were studied using a modified NAP test, which can contribute to the risk assessment of the drug. CONCLUSIONS: Forced degradation studies were conducted by establishing a SIAM for EDB. All the degradation products were characterized by mass spectral data obtained using LC/Q-TOF-HRMS.


Assuntos
Aminopiridinas , Nitrosaminas , Espectrometria de Massas por Ionização por Electrospray , Triazinas , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida/métodos , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Hidrólise , Oxirredução , Fotólise
15.
Mol Pharm ; 21(3): 1272-1284, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38361428

RESUMO

Rifampicin (RIF) is an antibiotic used to treat tuberculosis and leprosy. Even though RIF is a market-available drug, it has a low aqueous solubility, hindering its bioavailability. Among the strategies for bioavailability improvement of poorly soluble drugs, coamorphous systems have been revealed as an alternative in the increase of the aqueous solubility of drug systems and at the same time also increasing the amorphous state stability and dissolution rate when compared with the neat drug. In this work, a new coamorphous form from RIF and tromethamine (TRIS) was synthesized by slow evaporation. Structural, electronic, and thermodynamic properties and solvation effects, as well as drug-coformer intermolecular interactions, were studied through density functional theory (DFT) calculations. Powder X-ray diffraction (PXRD) data allowed us to verify the formation of a new coamorphous. In addition, the DFT study indicates a possible intermolecular interaction by hydrogen bonds between the available amino and carbonyl groups of RIF and the hydroxyl and amino groups of TRIS. The theoretical spectra obtained are in good agreement with the experimental data, suggesting the main interactions occurring in the formation of the coamorphous system. PXRD was used to study the physical stability of the coamorphous system under accelerated ICH conditions (40 °C and 75% RH), indicating that the material remained in an amorphous state up to 180 days. The thermogravimetry result of this material showed a good thermal stability up to 153 °C, and differential scanning calorimetry showed that the glass temperature (Tg) was at 70.0 °C. Solubility studies demonstrated an increase in the solubility of RIF by 5.5-fold when compared with its crystalline counterpart. Therefore, this new material presents critical parameters that can be considered in the development of new coamorphous formulations.


Assuntos
Rifampina , Trometamina , Composição de Medicamentos , Solubilidade , Água , Modelos Teóricos , Estabilidade de Medicamentos , Varredura Diferencial de Calorimetria , Difração de Raios X
16.
Int J Pharm Compd ; 28(1): 75-81, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38306623

RESUMO

The release of United States Pharmacopeia Chapter <800> and the revisions to United States Pharmacopeia Chapter <795> (official November 1, 2023) indicates a changing regulatory climate and a trend towards increasingly high standards for the extension of beyond-use dates beyond the default recommended by the guidelines. Given the increased scrutiny and the additional requirements for establishing extended beyond-use dates, additional testing is required to help pharmacies provide the best formulations with scientifically robust data to support an extended beyond-use date for patient convenience. The objective of this study was to demonstrate the suitability of two vehicles, Phytobase and HRT Heavy, for compounded hormone therapy by evaluating the stability and antimicrobial effectiveness of the vehicles with common combinations of hormones.


Assuntos
Farmácias , Humanos , Estabilidade de Medicamentos , Composição de Medicamentos
17.
Int J Pharm Compd ; 28(1): 82-86, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38306624

RESUMO

Aspirin is a non-steroidal, anti-inflammatory drug used for a range of indications. For patients with aspirin hypersensitivities, a desensitization procedure may be prescribed, and the initial low doses of <81 mg need to be provided by compounded preparations. Compounding with aspirin is associated with stability challenges due to its poor chemical stability. Additionally, low-strength preparations often exhibit dosage accuracy and uniformity issues. This study was designed to assess the feasibility of compounding low-strength aspirin capsules for the use in desensitization protocols. Aspirin capsules of 40-mg, 10-mg, 3-mg, and 1-mg strengths were prepared by manual filling of dry powders. Formulations were kept as simple as possible for ease of compounding, and the ingredients and compounding procedures were carefully selected to minimize the moisture content and to optimize the dosage accuracy. For the 40-mg and 10-mg capsules, two formulations were tested, using pure drug or crushed tablet powder. For the 3-mg and 1-mg capsules, only one formulation was tested, using a 5% mixture of pure drug and cellulose. All formulations were filled into hydroxypropyl methylcellulose capsule shells and stored at room temperature for 90 days. A  stability indicating, high-performance liquid chromatography method was used to analyze the quality of the capsules. The initial potency results of all capsule formulations were within 100% to 105% of the label claim, and the standard deviation was <3% for all formulations except the 1-mg strength (7%). The use of crushed tablet powder over pure drug powder appeared to reduce the potency variability, probably due to the larger fill weight per capsule. Upon storage at room temperature, the 40-mg and 10-mg formulations retained >90% of the label claim for up to 90 days, but the 3-mg and 1-mg formulations retained >90% of the label claim for up to only 31 days. Low-strength aspirin capsules were prepared successfully by compounding with a beyond-use date of at least 31 days at room temperature. However, the overall trend confirmed the challenges of achieving dosage uniformity and aspirin stability at 3-mg and 1-mg strengths. For general application in compounding pharmacies, trial batches are recommended with proper analytical testing.


Assuntos
Aspirina , Humanos , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Pós , Comprimidos , Cápsulas/química
18.
Chem Pharm Bull (Tokyo) ; 72(2): 190-199, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38369345

RESUMO

A co-amorphous model drug was prepared by the spray-drying (SD) of probucol (PC) and atorvastatin calcium trihydrate salt (ATO) as low water solubility and co-former components, respectively. The physicochemical properties of the prepared samples were characterized by powder X-ray diffraction (PXRD) analysis, thermal analysis, Fourier transform infrared spectroscopy (FTIR), and dissolution tests. Stability tests were also conducted under a stress environment of 40 °C and 75% relative humidity. The results of PXRD measurements and thermal analysis suggested that PC and ATO form a co-amorphous system by SD. Thermal analysis also indicated an endothermic peak that followed an exotherm in amorphous PC and a physical mixture (PM) of amorphous PC and ATO; however, no endothermic peak was detected in the co-amorphous system. The dissolution profiles for PC in the co-amorphous sample composed of PC and ATO were improved compared to those for raw PC crystals or the PM. Stability tests indicated that the co-amorphous material formed by PC and ATO can be stored for 35 d without crystallization, whereas amorphous PC became crystallized within a day. Therefore, co-amorphization of PC and ATO prepared by SD is considered to be a useful method to improve the solubility of PC in water.


Assuntos
Probucol , Água , Atorvastatina , Probucol/química , Estabilidade de Medicamentos , Cristalografia por Raios X , Difração de Raios X , Água/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Varredura Diferencial de Calorimetria
19.
Rapid Commun Mass Spectrom ; 38(7): e9712, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38351666

RESUMO

RATIONALE: Azelastine HCl is a second-generation H1 -receptor antagonist approved by the US Food and Drug Administration (US FDA) for treating seasonal allergic rhinitis and non-allergic vasomotor rhinitis. This study encompasses the validation of a liquid chromatography-ultra violet photo diode array (LC-UV/PDA) method for the drug and its extension to liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-Q/TOF-MS) studies for identification and characterization of various stress degradation products of the drug. METHODS: Stress degradation of azelastine HCl was undertaken under the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) prescribed conditions of hydrolytic, photolytic, oxidative, and thermal stress. The degraded drug solutions were analyzed using Ultra Performance Liquid Chromatography (UPLC) employing a C18 (100 × 4.6 mm; 2.6 µ, Kinetex) column by isocratic elution. Detection wavelength was 241 nm. The degradation products were identified and characterized using UPLC-MS/TOF studies, and an attempt was made to isolate one of the degradation products by solvent extraction. RESULTS: The drug was found to significantly degrade under acidic/alkaline/neutral photolytic, oxidative, and alkaline hydrolytic conditions. Six degradation products (I-VI) were identified through LC-Q/TOF-MS studies that were adequately resolved from the drug with the developed UPLC method. All degradation products (I-VI) were ionized in the total ion chromatogram (TIC) in the LC-MS studies, and these were identified and characterized, and the degradation pathway of the drug was postulated. One of the oxidation products isolated from the degraded drug solution was characterized through differential scanning calorimetry, Fourier-transform infrared spectroscopy, and nuclear magnetic resonance spectral data. CONCLUSIONS: Six degradation products generated from stress degradation studies on azelastine HCl were adequately resolved through LC-UV/PDA studies followed by method validation. These were successfully identified and characterized through LC-Q/TOF-MS studies, and the degradation pathways for the generation of these products from the drug have been postulated.


Assuntos
Ftalazinas , Espectrometria de Massas em Tandem , Humanos , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Preparações Farmacêuticas/análise , Estabilidade de Medicamentos , Hidrólise , Oxirredução , Cromatografia Líquida de Alta Pressão/métodos , Fotólise
20.
Mol Pharm ; 21(3): 1015-1026, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38288698

RESUMO

Vaccines have historically faced challenges regarding stability, especially in regions lacking a robust cold chain infrastructure. This review delves into established and emergent techniques to improve the thermostability of vaccines. We discuss the widely practiced lyophilization method, effectively transforming liquid vaccine formulations into a solid powdered state, enhancing storage and transportation ability. However, potential protein denaturation during lyophilization necessitates alternative stabilization methods. Cryoprotectants, namely, starch and sugar molecules, have shown promise in protecting vaccine antigens and adjuvants from denaturation and augmenting the stability of biologics during freeze-drying. Biomineralization, a less studied yet innovative approach, utilizes inorganic or organic-inorganic hybrids to encapsulate biological components of vaccines with a particular emphasis on metal-organic coordination polymers. Encapsulation in organic matrices to form particles or microneedles have also been studied in the context of vaccine thermostability, showing some ability to store outside the cold-chain. Unfortunately, few of these techniques have advanced to clinical trials that evaluate differences in storage conditions. Nonetheless, early trials suggest that alternative storage techniques are viable and emphasize the need for more comprehensive studies. This review underscores the pressing need for heat-stable vaccines, especially in light of the increasing global distribution challenges. Combining traditional methods with novel approaches holds promise for the future adaptability of vaccine distribution and use.


Assuntos
Temperatura Alta , Vacinas , Humanos , Estabilidade de Medicamentos , Composição de Medicamentos/métodos , Vacinação , Liofilização/métodos
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