RESUMEN
In this paper, we report two Accelerated Stability Assessment Program (ASAP) studies for a pediatric drug product. Whereas the first study using a generic design failed to establish a predictive model, the second one was successful after troubleshooting the first study and customizing the study conditions. This work highlighted important lessons learned from designing an ASAP study for formulations containing excipients that could undergo phase change at high humidity levels. The stability predictions by the second ASAP model were consistent with available long-term stability data of the drug product under various storage conditions in two different packaging configurations. The ASAP model was part of the justifications accepted by the health authority to submit a stability package with reduced long-term stability data from the primary stability batches for a Supplemental New Drug Application (sNDA).
Asunto(s)
Química Farmacéutica , Estabilidad de Medicamentos , Excipientes , Excipientes/química , Química Farmacéutica/métodos , Humedad , Almacenaje de Medicamentos , Embalaje de Medicamentos/métodos , Embalaje de Medicamentos/normas , Composición de Medicamentos/métodos , Humanos , Niño , Preparaciones Farmacéuticas/química , Pediatría/métodosRESUMEN
PURPOSE: The purpose of this work is to evaluate the interrelationship of microstructure, properties, and dissolution performance for amorphous solid dispersions (ASDs) prepared using different methods. METHODS: ASD of GDC-0810 (50% w/w) with HPMC-AS was prepared using methods of spray drying and co-precipitation via resonant acoustic mixing. Microstructure, particulate and bulk powder properties, and dissolution performance were characterized for GDC-0810 ASDs. In addition to application of typical physical characterization tools, we have applied X-Ray Microscopy (XRM) to assess the contribution of microstructure to the characteristics of ASDs and obtain additional quantification and understanding of the drug product intermediates and tablets. RESULTS: Both methods of spray drying and co-precipitation produced single-phase ASDs. Distinct differences in microstructure, particle size distribution, specific surface area, bulk and tapped density, were observed between GDC-0810 spray dried dispersion (SDD) and co-precipitated amorphous dispersion (cPAD) materials. The cPAD powders prepared by the resonant acoustic mixing process demonstrated superior compactibility compared to the SDD, while the compressibility of the ASDs were comparable. Both SDD powder and tablets showed higher in vitro dissolution than those of cPAD powders. XRM calculated total solid external surface area (SA) normalized by calculated total solid volume (SV) shows a strong correlation with micro dissolution data. CONCLUSION: Strong interrelationship of microstructure, physical properties, and dissolution performance was observed for GDC-0810 ASDs. XRM image-based analysis is a powerful tool to assess the contribution of microstructure to the characteristics of ASDs and provide mechanistic understanding of the interrelationship.
Asunto(s)
Liberación de Fármacos , Solubilidad , Polvos , Composición de Medicamentos/métodos , Comprimidos/químicaRESUMEN
In this study, a multipronged approach of in vitro experiments, in silico simulations, and in vivo studies was developed to evaluate the dissolution, supersaturation, precipitation, and absorption of three formulations of Compound-A, a BCS class 2 weak base with pH-dependent solubility. In in vitro 2-stage dissolution experiments, the solutions were highly supersaturated with no precipitation at the low dose but increasing precipitation at higher doses. No difference in precipitation was observed between the capsules and tablets. The in vitro precipitate was found to be noncrystalline with higher solubility than the crystalline API, and was readily soluble when the drug concentration was lowered by dilution. A gastric transit and biphasic dissolution (GTBD) model was developed to better mimic gastric transfer and intestinal absorption. Precipitation was also observed in GTBD, but the precipitate redissolved and partitioned into the organic phase. In vivo data from the phase 1 clinical trial showed linear and dose proportional PK for the formulations with no evidence of in vivo precipitation. While the in vitro precipitation observed in the 2-stage dissolution appeared to overestimate in vivo precipitation, the GTBD model provided absorption profiles consistent with in vivo data. In silico simulation of plasma concentrations by GastroPlus using biorelevant in vitro dissolution data from the tablets and capsules and assuming negligible precipitation was in line with the observed in vivo profiles of the two formulations. The totality of data generated with Compound-A indicated that the bioavailability differences among the three formulations were better explained by the differences in gastric dissolution than intestinal precipitation. The lack of intestinal precipitation was consistent with several other BCS class 2 basic compounds in the literature for which highly supersaturated concentrations and rapid absorption were also observed.
Asunto(s)
Absorción Intestinal/fisiología , Preparaciones Farmacéuticas/metabolismo , Comprimidos/metabolismo , Disponibilidad Biológica , Biofarmacia/métodos , Química Farmacéutica/métodos , Simulación por Computador , Humanos , Intestinos/química , Solubilidad , Estómago/fisiologíaRESUMEN
In this study, two dissolution models were developed to achieve in vitro-in vivo relationship for immediate release formulations of Compound-A, a poorly soluble weak base with pH-dependent solubility and low bioavailability in hypochlorhydric and achlorhydric patients. The dissolution models were designed to approximate the hypo-/achlorhydric and normal fasted stomach conditions after a glass of water was ingested with the drug. The dissolution data from the two models were predictive of the relative in vivo bioavailability of various formulations under the same gastric condition, hypo-/achlorhydric or normal. Furthermore, the dissolution data were able to estimate the relative performance under hypo-/achlorhydric and normal fasted conditions for the same formulation. Together, these biorelevant dissolution models facilitated formulation development for Compound-A by identifying the right type and amount of key excipient to enhance bioavailability and mitigate the negative effect of hypo-/achlorhydria due to drug-drug interaction with acid-reducing agents. The dissolution models use readily available USP apparatus 2, and their broader utility can be evaluated on other BCS 2B compounds with reduced bioavailability caused by hypo-/achlorhydria.
Asunto(s)
Aclorhidria/complicaciones , Liberación de Fármacos , Modelos Químicos , Administración Oral , Disponibilidad Biológica , Química Farmacéutica , Interacciones Farmacológicas , Humanos , Concentración de Iones de Hidrógeno , Solubilidad , ComprimidosRESUMEN
This study evaluated the impact of mucin on supersaturation and permeation of BCS Class 2 basic drugs in a pH-shift, 2-stage model using three model compounds, dipyridamole, ricobendazole, and Compound A. The three compounds showed various degrees of supersaturation (DoS) in Stage 2 and modest to no increases in flux with the presence of mucin in the dissolution media. Mucin's impact on DoS and flux, if any, appeared to be compound specific and possibly related to its pKa and ionization state. Overall, the increases in supersaturation and permeation due to mucin ranged from modest to minimal for the three model compounds under the conditions tested. The pH-shift model using MacroFLUX was able to monitor gastric and intestinal dissolution and simultaneously assess the effect of intestinal mucin on supersaturation and flux.
RESUMEN
This paper systematically investigated and reported for the first time the identification and quantification of co-eluting impurities as low as 0.05 area% by PDA with i-PDeA II deconvolution software in the LabSolutions Chromatographic Data System (CDS) using an integrated multivariate curve resolution-alternating least squares (MCR-ALS) algorithm with a bidirectional exponentially modified Gaussian (BEMG) model function. The algorithm was able to consistently identify 0.05% impurities when co-eluting with the main component (Rs ≥ 0.8) as well as when co-eluting with another impurity (Rs ≥ 0.5). In the case of two co-eluting impurities from 0.05% to 1% (Rs ≥ 0.5), the quantification error ranged from +10.6% to -16.7%. In the case of an impurity co-eluting with the main component (Rs ≥ 0.8), the quantification error was 4.4-8.9% for 1% impurity and 109-184% for 0.05% impurity. The precision was excellent for the range of 0.05-1.0% impurities with the RSD being 1.4-3.0% for 1% impurity and 4.0-8.7% for 0.05% impurity. The identification rate and quantitation accuracy were not affected by the spectral similarity of the molecules, as comparable results were obtained by analyzing two molecules with low similarity (4,4-difluorobenzophenone and valerophenone) and two molecules with high similarity (diazepam and oxazepam) based on simulated data. This peak resolution by MCR-ALS approach provides fast and robust identification and quantification of co-eluting impurities even when method development efforts do not provide complete separation of the target peaks, and could therefore find a wide range of applications in pharmaceutical and other types of analyses.
Asunto(s)
Algoritmos , Programas Informáticos , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida , Análisis de los Mínimos Cuadrados , Análisis Multivariante , Preparaciones FarmacéuticasRESUMEN
Haloacetic acids are an important class of disinfection byproducts that are being regulated. In this paper we report novel instrumentation for continuous monitoring of the nine haloacetic acids. Hollow fiber liquid-liquid membrane extraction (LLME) and supported liquid membrane extraction (SLME) followed by on-line HPLC-UV detection were studied. With continuous LLME, seven halo-acetic acids could be analyzed and enrichment factor (EF) was around 50. All the nine acids could be extracted and quantified by continuous SLME. Experiments with laboratory standards demonstrated that EF and extraction efficiency could be as high as 500 and 54%, respectively. Relative standard deviations based on seven replicates were between 3.3 and 10.3%, and the MDLs were at sub-ppb levels.
Asunto(s)
Acetatos/análisis , Membranas Artificiales , Cromatografía Líquida de Alta Presión/métodos , Halógenos/química , Espectrofotometría UltravioletaRESUMEN
Supported liquid membrane microextraction (SLMME) with high-performance liquid chromatography (HPLC)-UV detection has been developed for the extraction, preconcentration, and determination of all the nine haloacetic acids (HAAs) in water. The HAAs are extracted into a supported liquid membrane, and then back-extracted into few microliters of an acceptor solution. The extract was directly analyzed by HPLC-UV with a 15-min run. Enrichment factors in the range of 300-3000 were obtained in a 60-min extraction, and detection limits were at low to sub-microg/L level with R.S.D. values between 1.5 and 10.8%. The parameters that affected analyte enrichment were studied. This approach offers an attractive alternative to the current US Environmental Protection Agency standard methods for HAA analysis, which require complex sample preparation and derivatization prior to analysis by gas chromatography. SLMME can also be used in conjunction with other analytical schemes, such as, ion chromatography and capillary electrophoresis.
Asunto(s)
Acetatos/análisis , Cromatografía Líquida de Alta Presión/métodos , Halógenos/análisis , Espectrofotometría Ultravioleta/métodos , Abastecimiento de Agua/análisis , Reproducibilidad de los ResultadosRESUMEN
A technique of using size exclusion chromatography (SEC) with the Corona charged aerosol detector (CAD) was developed and evaluated in comparison with refractive index (RI) and evaporative light scattering detection (ELSD) for fast screening of polyethylene glycol (PEG), a polymer used in preparing pegylated pharmaceutical compounds. These detection techniques were used in the analysis of multiple lots of PEG reagents. CAD was found to provide more accurate impurity and polydispersity profiles of PEG reagents that better differentiate their quality, while RI was not suitable for this application due to its low sensitivity and ELSD led to underestimation of the impurity and polydispersity. The accuracy of polydispersity determination by SEC-CAD was validated against a commercial reference standard of known polydispersity. The SEC-CAD technique and the observed differences between the three detectors can also be applied to polymer analysis in general.
Asunto(s)
Aerosoles/química , Cromatografía en Gel , Polietilenglicoles/análisis , Cromatografía en Gel/instrumentación , Cromatografía en Gel/métodos , Contaminación de Medicamentos , Luz , Modelos Lineales , Peso Molecular , Refractometría/métodos , Reproducibilidad de los Resultados , Dispersión de Radiación , Sensibilidad y EspecificidadRESUMEN
In the determination of trace-level pollutants in water, a concentration step is usually needed between extraction and analysis. In this paper, simultaneous extraction and concentration during on-line analysis using hollow fiber membranes is reported. Solvent loss across the membrane resulted in simultaneous concentration during extraction and had pronounced influence on enrichment factor and extraction efficiency. This phenomenon is an important consideration for analytical methods employing solvent extraction across a membrane, because it is possible to eliminate the concentration step. Continuous on-line monitoring of semivolatile compounds was achieved using this approach, and the effects of process variables on enrichment and extraction efficiency were studied. It was found that enrichment increased with solvent loss, even when the extraction efficiency decreased.