Characterization of in vitro and in vivo drug release profiles constitutes an important step in developing and optimizing an effective, long acting delivery system for naltrexone. Accelerated in vitro methods are also important for quality assurance of manufactured dosage forms. For drug release testing of sustained release parenteral dosage forms, the modified USP Apparatus 4 (flow-through cell) has been recommended by the The Fédération Internationale Pharmaceutique/American Association of Pharmaceutical Scientists (FIP/AAPS) Guidelines. Details on such studies however, are generally not found in the literature. To incorporate 'biorelevance' to implant drug release studies, this research investigated an approach to apparatus design and media selection that is significantly different from conventional dissolution studies involving oral dosage forms.Biodegradable implants of naltrexone were obtained from Durect Corporation, USA. A modified Hanks' Balanced Salts Solution was characterized as a 'biorelevant' medium for in vitro drug release studies. Naltrexone was found to be sufficiently stable in the medium, as determined by a stability-indicating High Performance Liquid Chromatography (HPLC) assay. A miniature, cell-culture, capillary system was modified and tested as a 'biorelevant' alternative to the modified flow-through apparatus, to mimic significant barriers to drug release that would be expected in vivo. The in vitro release profiles generated up to 3 months using both devices indicated considerable (2-fold) variation in rates, as expected from the difference in media flow characteristics. An implantation study in a dog was conducted to determine which of the two devices could provide a better simulation of the in vivo conditions. Analysis of in vivo samples was carried out by a Liquid Chromatography-Tandem Mass Spectrometry (LC-MS-MS) method that also employed a molecular model approach to demonstrate the absence of Internal Standard Deuterium Isotope Effects. A good In vitro-In vivo Correlation (IVIVC) resulted from both devices; however, the capillary device provided a superior simulation for the lag-time in absorption. The accelerated study at 45°C and 55°C established a predictable increase in release rates (2-fold and 4-fold increases, respectively). The approach described in this work could provide the basis for future method modification of in vitro drug release tests of subcutaneous implants.

Herewith are presented the results of an investigation the statistical power of USP compendial release tests and recommended alternatives. <br>The U.S. drug supply chain, formerly protected by a closed distribution network, is now threatened by the legal and illegal importation of drug products. Whereas quality can never be inspected into final products, compendial release standards may represent the only valid assessment that products of dubious origin would receive. Reliable tests for content uniformity and dissolution are required to protect the safety of the supply chain. A study was designed to test the hypothesis that existing compendial tests for content uniformity and dissolution would protect the supply chain against substandard and counterfeit drugs if basic field tests failed. <br>Compendial tests for content uniformity and dissolution were evaluated for statistical power using simulation studies. The results revealed that the revised content uniformity test, based on tolerance analysis, was subject to an unacceptable level of consumers' risk. The Bergum method proved to be an excellent secondary standard for product assessment and is recommended as an alternative to the USP method. Simulations with the USP dissolution test revealed significant weaknesses and inconsistencies in the test structure. Theoretical models and power assessments confirmed that the coverage specification of the dissolution test was an unacceptably high 50% coverage with 50% confidence. <br>A Bayesian D-optimal design program was used to investigate alternative methods to improve the coverage capability of the USP dissolution test. The result of this program was the identification of two alternatives to the existing USP procedure. The first alternative is based on the addition of attribute coverage tests to stages 2 and 3 of the USP test, whereas the second alternative is based on the concept of tolerance analysis. <br>Validation studies confirmed that both alternatives significantly improved the statistical power of the USP dissolution test without increasing the sample size or modifying the current three-stage procedure. The attribute test is non-parametric and behaves similarly to the existing USP with improved coverage, whereas the continuous alternative is more sensitive and is consistent with the recent revisions to the content uniformity test. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences / Pharmaceutics / PhD / Dissertation

The unique symmetry requirements of second harmonic generation (SHG) provide exquisite selectivity to chiral crystals, enabling independent quantitative modeling of the nucleation and crystal growth of active pharmaceutical ingredients (APIs) within amorphous solid dispersions (ASDs) during accelerated in situ stability testing, and in vitro dissolution testing. ASDs, in which an API is maintained in an amorphous state within a polymer matrix, are finding increasing use to address solubility limitations of small-molecule APIs. SHG microscopy yielded limits of detection for ritonavir crystals as low as 10 ppm, which is about two orders of magnitude lower than other methods currently available for crystallinity detection in ASDs. The quantitative capabilities of SHG analysis were substantially improved further while simultaneously dramatically reducing the total sample volume and storage burden through in situ analysis. Single particle tracking of crystal growth performed in situ enabled substantial improvements in the signal to noise ratio (SNR) for recovered crystal nucleation and growth rates by nonlinear optical microscopy. Upon dissolution, the presence of solubilizing additives in biorelevant media greatly affected the generation and stabilization of supersaturated solutions. SHG microscopy was found to enable the detection of crystals even in the highly turbid Ensure Plus® system. Analysis of the SHG micrographs clearly indicated that differences in the nucleation kinetics rather than growth rates dominated the overall trends in crystallinity. For weakly basic drugs, the fate of dissolution in fasted-state simulated intestinal fluid (FaSSIF, pH 6.5) varied with the ASDs drug loading, and was highly affected by the pre-exposure to the fasted-state simulated gastric fluid (FaSSGF, pH 1.6) medium, versus the dissolution in FaSSIF medium alone. The presence of crystals during the first stage of posaconazole ASDs dissolution in FaSSGF acted as nuclei for further crystallization in the later dissolution stage in FaSSIF. The results provide insights of better formulation prediction of poorly soluble drugs, as well as understanding origins of intraluminal absorption variability for such systems

目前在國內外藥界對比對溶離資料之處理方法有很多種.在本文以常用之二維隨機集區實驗設計,共變異數分析法,單變量分裂區集變異析法,Chow(1995)所提出之時間數列分析法,及美國食品藥物管理局在1995年11月所提出的方法,比較此五種方法並以電腦模擬不同情形之資料再對其結果予以分析. / There are various ways of comparing dissolution profiles between two drug products. In this thesis, we compare five statistical methods often used,namely, two-way randomized block design, analysis of covariance, split-plot,time-series analysis method proposed by Chow (1995), and the method proposed by Food and Drug Administration (FDA) in November, 1995. The five methods are compared via simulation studies under different conditions, analyses arealso provided.

Résumé : À partir de 2002, grâce à l’introduction du concept de la Qualité par la Conception (en anglais Quality by Design : QbD) par l’agence américaine des produits alimentaires et médicamenteux, l’industrie pharmaceutique a intensifié les efforts et les investissements pour permettre une libération en temps réel des lots commerciaux. Le QbD propose que la qualité soit construite dès la conception initiale du médicament plutôt que d'être évaluée à la fin de sa fabrication. Ainsi, avec l’initiative QbD, les tests de contrôle de la qualité des médicaments, réalisés après la fabrication des comprimés, peuvent être éliminés si les paramètres qui les influencent sont contrôlés. En effet, ces tests de contrôle qualité dits traditionnels requièrent en général plusieurs heures pour leurs préparations et leurs réalisations. Tel est le cas du test de dissolution. Ce test est très consommateur de ressources matérielles et humaines. La réalisation de stratégies de contrôle pour les tests de dissolution basée sur une approche QbD pourrait être bénéfique pour l'industrie pharmaceutique. À travers ce travail, nous avons pu : • proposer différentes stratégies novatrices de contrôle du test de dissolution de comprimés pharmaceutiques sur la base des principes du QbD, • apporter un nouvel éclairage sur la compréhension des phénomènes impliqués dans la dissolution de comprimés pharmaceutiques. Les résultats de ce projet de recherche ont permis 1) la mise en évidence des paramètres critiques influençant le test de dissolution, 2) l’élaboration et l’évaluation de modèles statistiques pour les combinaisons de variation de paramètres selon un plan d’expérience préalablement conçu, 3) la corrélation du test de dissolution à des paramètres critiques de procédés de fabrication et d’attributs de matériaux grâce aux technologies d’analyse de procédés. // Abstract : With the introduction in 2002 of the concept of Quality by Design (QbD) by the Food and Drug Administration, the pharmaceutical industry intensified efforts and investments to reach real time release of commercial batches, reducing time between manufacturing and availability to the patient. QbD proposes that quality should be built in the initial design of a product rather than being assessed at the end of the tablet manufacturing. Thus, with the QbD initiative, quality control tests of tablets like dissolution testing performed after manufacturing could be removed if the parameters impacting them are controlled. Indeed, quality control tests such as traditional dissolution tests generally require several hours for their preparation and their realizations. Dissolution tests are time consuming, require large amounts of material and human resources. The elimination of these tests through a QbD approach could be beneficial for the pharmaceutical industry. Thanks to this work, it was possible to :  propose different innovative strategies to control the dissolution test of pharmaceutical tablets based on the principles of Quality by Design,  have a better understanding of this quality control test. The main results relies on 1) the identification of critical parameters influencing the dissolution test, 2) the development and evaluation of statistical models for the combination of variation of parameters according to an experimental design, 3) the correlation of dissolution test to critical manufacturing process parameters and attributes of materials through process analysis technology.

A partir de 2002, grâce à l'introduction du concept de la Qualité par la Conception (en anglais Quality by Design : QbD) par l'agence américaine des produits alimentaires et médicamenteux, l'industrie pharmaceutique a intensifié les efforts et les investissements pour permettre une libération en temps réel des lots commerciaux. Le QbD propose que la qualité soit construite dès la conception initiale du médicament plutôt que d'être évaluée à la fin de sa fabrication. Ainsi, avec l'initiative QbD, les tests de contrôle de la qualité de médicaments, réalisés après la fabrication des comprimés, peuvent être éliminés si les paramètres qui les influencent sont contrôlés.En effet, ces tests de contrôle qualité dits traditionnels requièrent en général plusieurs heures pour leurs préparations et leurs réalisations. Tel est le cas du test de dissolution. Ce test est très consommateur de ressources matérielles et humaines. La réalisation de stratégies de contrôle pour les tests de dissolution basée sur une approche QbD pourrait être bénéfique pour l'industrie pharmaceutique.À travers ce travail, nous avons pu :• proposer différentes stratégies novatrices de contrôle du test de dissolution de comprimés pharmaceutiques sur la base des principes du QbD,• apporter un nouvel éclairage sur la compréhension des phénomènes impliqués dans la dissolution de comprimés pharmaceutiques.Les résultats de ce projet de recherche ont permis 1) la mise en évidence des paramètres critiques influençant le test de dissolution, 2) l'élaboration et l'évaluation de modèles statistiques pour les combinaisons de variation de paramètres selon un plan d'expérience préalablement conçu, 3) la corrélation du test de dissolution à des paramètres critiques de procédés de fabrication et d'attributs de matériaux grâce aux technologies d'analyse de procédés. / With the introduction in 2002 of the concept of Quality by Design (QbD) by the Food and Drug Administration, the pharmaceutical industry intensified efforts and investments to reach real time release of commercial batches, reducing time between manufacturing and availability to the patient. QbD proposes that quality should be built in the initial design of a product rather than being assessed at the end of the tablet manufacturing. Thus, with the QbD initiative, quality control tests of tablets like dissolution testing performed after tablets manufacturing could be removed if the parameters impacting them are controlled.Indeed, quality control tests such as traditional dissolution tests generally require several hours for their preparation and their realizations. Dissolution tests are very consuming of time, material, equipment and human resources. The elimination of these tests through a QbD approach could be beneficial for the pharmaceutical industry.Thanks to this work, it was possible to :• propose different innovative strategies to control the dissolution test of pharmaceutical tablets based on the principles of Quality by Design,• have a better understanding of this quality control test.The main results relies on 1) the identification of critical parameters influencing the dissolution test, 2) the development and evaluation of statistical models for the combination of variation of parameters according to an experimental design, 3) the correlation of dissolution test to critical manufacturing process parameters and attributes of materials through process analysis technology.