RESUMEN
In an earlier investigation, the critical cooling rate to prevent drug crystallization (CRcrit) during the preparation of nifedipine (NIF) amorphous solid dispersions (ASDs) was determined through a time-temperature transformation (TTT) diagram (Lalge et al. Mol. Pharmaceutics 2023, 20 (3), 1806-1817). The current study aims to use the TTT diagram to determine the critical cooling rate to prevent drug nucleation (CRcrit N) during the preparation of ASDs. ASDs were prepared with each polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS). The dispersions were first stored under conditions promoting nucleation and then heated to the temperature that favors crystallization. The crystallization onset time (tC) was determined by differential scanning calorimetry and synchrotron X-ray diffractometry. TTT diagrams for nucleation were generated, which provided the critical nucleation temperature (50 °C) and the critical cooling rate to avoid nucleation (CRcrit N). The strength of the drug-polymer interactions as well as the polymer concentration affected the CRcrit N, with PVP having a stronger interaction than HPMCAS. The CRcrit of amorphous NIF was â¼17.5 °C/min. The addition of a 20% w/w polymer resulted in CRcrit of â¼0.05 and 0.2 °C/min and CRcrit N of â¼4.1 and 8.1 °C/min for the dispersions prepared with PVP and HPMCAS, respectively.
Asunto(s)
Polímeros , Povidona , Temperatura , Povidona/química , Polímeros/química , Cristalización , Transición de Fase , Solubilidad , Metilcelulosa/química , Estabilidad de MedicamentosRESUMEN
The critical cooling rate (CRcrit) to prevent drug crystallization during the preparation of nifedipine amorphous solid dispersions (ASDs) was determined through the time-temperature-transformation (TTT) diagram. ASDs were prepared with polyvinylpyrrolidone, hydroxypropylmethyl cellulose acetate succinate, and poly(acrylic acid). ASDs were subjected to isothermal crystallization over a wide temperature range, and the time and temperature dependence of nifedipine crystallization onset time (tC) was determined by differential scanning calorimetry (DSC) and synchrotron X-ray diffractometry. TTT diagrams were generated for ASDs, which provided the CRcrit for the dispersions prepared with each polymer. The observed differences in CRcrit could be explained in terms of differences in the strength of interactions. Stronger drug-polymer interactions led to longer tC and decreased CRcrit. The effect of polymer concentrations (4-20% w/w) was also influenced by the strength of the interaction. The CRcrit of amorphous NIF was â¼17.5 °C/min. Addition of 20% w/w polymer resulted in a CRcrit of â¼0.05, 0.2, and 11 °C/min for the dispersions prepared with PVP, HPMCAS, and PAA, respectively.
Asunto(s)
Nifedipino , Polímeros , Polímeros/química , Cristalización , Temperatura , Nifedipino/química , Povidona/química , Solubilidad , Rastreo Diferencial de CalorimetríaRESUMEN
Drugs containing an amino aromatic nitrogen moiety were stabilized in the amorphous form by the surfactant cholic acid (CA). Coamorphous systems of lamotrigine (LAM), pyrimethamine (PYR), and trimethoprim (TRI) were each prepared with CA. Drug-CA interactions, investigated by IR and solid-sate NMR spectroscopy, revealed deprotonation of the carboxylic acid group in CA and the protonation of the most basic nitrogen of the drug. The coamorphous systems exhibited exceptional physical stability and resisted crystallization at (i) elevated temperatures (>100 °C) and (ii) accelerated storage conditions, 40 °C/75% relative humidity for 15 months. The dissolution performance of each coamorphous system was compared with the respective crystalline drug based on the area under the curve (AUC) of the concentration-time profiles. A 25-fold increase in AUC was observed in the PYR-CA coamorphous system. The solubility enhancement is attributed not only due to drug amorphization but also due to solubilization by CA. The supramolecular synthon approach, through a drug-CA interaction, yielded physically stable coamorphous systems with enhanced aqueous drug solubility.
Asunto(s)
Ácidos y Sales Biliares , Excipientes , Rastreo Diferencial de Calorimetría , Estabilidad de Medicamentos , Excipientes/química , Nitrógeno , SolubilidadRESUMEN
Disproportionation of pioglitazone hydrochloride (PioHCl), leading to the free base formation, was observed in tablet formulations containing basic excipients such as magnesium stearate (Koranne et al, Mol. Pharmaceutics, 2017, 14, 1133-1144). The nature and concentration of excipients, by modulating the microenvironmental acidity (measured as pHeq), governed the disproportionation reaction. In the current work, we hypothesized that the addition of an organic acid, by lowering the pHeq, can stabilize PioHCl. Powder blends containing PioHCl, magnesium stearate and each oxalic, maleic, tartaric, fumaric, and glutaric acid were stored at 40 °C/75% RH for 15 days. The concentration of crystalline free base, a product of the disproportionation reaction, was quantified using synchrotron radiation. The pHeq of the powder blends was measured via ionization of probe molecules deposited on the surface. In general, the stronger the acid, the lower the pHeq of the formulation blend and more effective it was in stabilizing PioHCl and preventing disproportionation. Thus, controlling the microenvironmental acidity in a rational and systematic way provided an avenue to mitigate excipient-induced salt disproportionation. Even when the lattice of PioHCl was activated by milling, it remained stable in the presence of acid. The amount of water sorbed during tablet storage provided an indirect measure of the disproportionation.
Asunto(s)
Ácidos/química , Pioglitazona/química , Sales (Química)/química , Química Farmacéutica/métodos , Composición de Medicamentos/métodos , Excipientes/química , Concentración de Iones de Hidrógeno , Polvos/química , Solubilidad , Comprimidos/química , Agua/químicaRESUMEN
Cefuroxime Axetil (CA) is a poorly soluble, broad spectrum antibiotic which undergoes enzymatic degradation in gastrointestinal tract. The objective of the present study was to develop lipid-based gastro-retentive floating drug delivery systems containing CA using hot-melt extrusion (HME) to improve absorption. Selected formulations of CA and lipids were extruded using a twin screw hot-melt extruder. Milled extrudates were characterized for dissolution, floating strength, and micromeritic properties. Solid-state characterization was performed using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, and hot-stage microscopy. In vitro characterization demonstrated that the formulations exhibited a sustained drug release profile for 12â¯h. All formulations showed desired floating and flow properties. Solid-state characterization revealed no phase separation and no chemical interactions between the drug and excipients. Based on in vitro study results, an optimized formulation (F8) was further evaluated for in vivo performance. Oral bioavailability (Cmax and AUC0-24h) of F8 was significantly higher than that of pure CA. This study describes the use of lipid-based gastro-retentive floating drug delivery systems to achieve desired sustained release profile for more complete dissolution which could potentially reduce enzymatic degradation. This study also highlights the effectiveness of HME technology to improve dissolution and bioavailability.
Asunto(s)
Antibacterianos/administración & dosificación , Cefuroxima/análogos & derivados , Sistemas de Liberación de Medicamentos , Administración Oral , Animales , Antibacterianos/sangre , Antibacterianos/química , Antibacterianos/farmacocinética , Disponibilidad Biológica , Cefuroxima/administración & dosificación , Cefuroxima/sangre , Cefuroxima/química , Cefuroxima/farmacocinética , Composición de Medicamentos , Liberación de Fármacos , Tecnología de Extrusión de Fusión en Caliente , Masculino , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Ratas Sprague-Dawley , Estómago/fisiologíaRESUMEN
The choice of excipients constitutes a major part of preformulation and formulation studies during the preparation of pharmaceutical dosage forms. The physical, mechanical, and chemical properties of excipients affect various formulation parameters, such as disintegration, dissolution, and shelf life, and significantly influence the final product. Therefore, several studies have been performed to evaluate the effect of drug-excipient interactions on the overall formulation. This article reviews the information available on the physical and chemical instabilities of excipients and their incompatibilities with the active pharmaceutical ingredient in solid oral dosage forms, during various drug-manufacturing processes. The impact of these interactions on the drug formulation process has been discussed in detail. Examples of various excipients used in solid oral dosage forms have been included to elaborate on different drug-excipient interactions.