Application of 1-Dimensional and 2-Dimensional Solid-State Nuclear Magnetic Resonance Spectroscopy to the Characterization of Morphine, Morphine Hydrochloride, and Their Hydrates.

The detailed knowledge of the solid forms of a drug is a key element in pharmaceutical development. Morphine (MOR) is an opiate alkaloid widely used to treat severe acute and chronic pain. Much of the available information on its solid state dates from several decades ago. In order to obtain updated and reliable information, 1-dimensional (1D) and 2-dimensional solid-state nuclear magnetic resonance spectroscopy were used and complemented with powder X-ray diffraction, FTIR, and Raman spectroscopy and thermal analysis. 13C cross-polarization with magic angle spinning 1D spectra accomplish a complete identification of the related forms of MOR. Remarkably, 1H-13C heteronuclear correlation spectra together with FTIR results gave clear evidence that neither MOR nor its hydrate crystallizes as a zwitterion. Our results indicate that the hydrogen bonds in the anhydrate forms have a different nature or strength than in their respective hydrates. The unique information obtained would be useful for the characterization of MOR as a bulk drug, dosage forms, and future developments.

Analgesia enhancement and prevention of tolerance to morphine: beneficial effects of combined therapy with omega-3 fatty acids.

OBJECTIVES: Recent evidence associates omega-3 fatty acids (O3) with pain reduction. The aim of this work was to evaluate the antinociceptive effect of O3, either alone or in combination with morphine after acute and chronic administration in rats. As well, a new pharmaceutical mixture that allows the concomitant administration of O3 and morphine as an oral solution was developed. METHODS: Animals were fed on a control or an experimental diet supplemented with O3. They were subjected to the hot-plate test to assess analgesic effect and tolerance to the analgesic effect of morphine. The open-field test was carried out to determine if the differences in the response latency can be related to non-specific sedative effects. KEY FINDINGS: O3 dietary supplementation increased the response latency compared with the control group. Acute treatment with morphine in these groups resulted in an additive antinociceptive effect not related to locomotor activity. Chronic coadministration of morphine with O3 attenuated the development of tolerance. Oral administration of the new pharmaceutical mixture showed analgesic activity with a subtherapeutic dose of morphine. CONCLUSION: This finding suggests a role for O3 as adjuncts to opioids in pain therapy and might contribute to the reduction of the occurrence of morphine side-effects.

Diseño y preparación de formas farmacéuticas sólidas de Benznidazol para el tratamiento de la Enfermedad de Chagas / Design and Preparation fo Pharmaceutical Solid Dosage Forms of Benznidazole for the Treatment of Chagas Disease

INTRODUCCIÓN: En Argentina se emplea el benznidazolcomo terapéutica de primera línea para el tratamiento etiológico del Chagas. Desde su lanzamiento (hace más de 40 años), sólo se dispone de comprimidos convencionales de 100 mg; no se han desarrollado nuevas formas farmacéuticas que aumenten la eficacia y seguridad, ni alternativas con dosis pediátricas. OBJETIVOS: Desarrollar formas farmacéuticas de benznidazol que ofrezcan ventajas farmacoterapéuticas. MÉTODOS: Preformulación y diseño de nuevas formulaciones de benznidazol, con caracterización físico-química y selección de las formulaciones más favorables. Frente a la discontinuidad de producción del ingrediente activo benznidazol, se desarrolló una metodología de extracción a partir de 8520/8520/nica alternativa comercial disponible. RESULTADOS: Se obtuvieron nuevas formulaciones de comprimidos de 50 y 100 mg debenznidazol, con una rápida disolución del producto de referencia. Además, se obtuvieron formulaciones masticables de 50 mg bajo la forma de hidrogeles azucarados, con un efectivo enmascaramiento del mal sabor. Todas las formulaciones cumplieron los ensayos de evaluación de las propiedades farmacotécnicas y biofarmacéuticas, superando los perfiles de referencia. CONCLUSIONES: Se desarrollaron nuevas alternativas farmacéuticas de benznidazol de rápida disolución, que podrían mejorar el tratamiento etiológico de la enfermedad(especialmente en pediatría) y convertirse en herramientas aptas para su explotación comercial

INTRODUCTION: In Argentina, benznidazole is the drug of choice for the etiological treatment of Chagas disease. Since it was launched (more than 40 years ago), there are only 100 mg tablets available; the development included neither new pharmaceutical forms improving efficacy and safety, nor a pediatric dosage option. OBJECTIVES: To develop pharmaceutical form sof benznidazole with pharmacotherapeutic advantages. METHODS: Preformulation and design of new formulation sof benznidazole, with physicochemical characterization and selection of the most favorable formulations. Due to the discontinuity in the production of the active ingredient benznidazole, a specific methodology was developed in order to obtain it from the only commercially available alternative. RESULTS: New benznidazole tablet formulations were obtained (50 and 100 mg), with a rapid dissolution of the reference product, as well as chewable formulation sof 50 mg as sugar hydrogels featuring an effective taste masking. All formulations passed the evaluation tests for pharmacotechnical and biopharmaceutical properties, out performing the reference profiles. CONCLUSIONS:New fast-dissolving pharmaceutical dosage forms of benznidazole were developed, which could improve the etiological treatment of the disease (especially in the pediatric field) and become a proper tool for its commercial exploitation

Desarrollo de nuevos sistemas de liberación modificada y administración oral para el tratamiento de la tuberculosis / Development of new oral drug delivery systems for tuberculosis treatment

INTRODUCCIÓN: Rifampicina es inestable en medio ácido, y su descomposición es acelerada por isoniazida. El desarrollo de una formulación que permita la iberación secuencial de rifampicina (en estómago) e isoniazida (en intestino) podría superar este inconveniente. OBJETIVO: Obtener materiales portadores de rifampicina e isoniazida mediante acomplejamiento con polielectrolitos y caracterizarlos para determinar su utilidad en el desarrollo de sistemas de liberación sitio-específica, en combinación a dosisfija. MÉTODOS: Se utilizaron carboximetilcelulosa (CMC) y ácidoalgínico (AA) como polielectrolitos modelo. Se obtuvieron series de complejos CMC-rifampicina y AA-isoniazida. Se caracterizó el tipo de interacción, la capacidad de carga y las características reológicas de los materiales sólidos que, tras ser compactados bajo la forma de matrices simples o mixtas, fueron sometidos a ensayos de liberación en medios biorrelevantes. RESULTADOS: La interacción entre los grupos involucrados fue iónica, con una capacidad de carga del 100%. Los materiales presentaron propiedades de flujo desfavorables, con mejora por granulación. Las matrices liberaron rápidamente rifampicina en medio ácido con mínimos niveles concomitantes de isoniazida. La matriz seleccionada presentó liberación modulada de isoniazida, completada al cabo de 3 horas en un medio que simulaba el contenido intestinal. CONCLUSIONES: Los nuevos materiales pueden ser utilizados en el desarrollo de una formulación oral de liberación sitio-específica, capaz de mejorar la efectividad, reducir efectos adversos e incrementar la estabilidad de rifampicina.

INTRODUCTION: Rifampicin is unstable in acidic medium and its decomposition is accelerated by isoniazid. The development of a formulation to allow the sequential release of rifampicin (in stomach) and isoniazid (in gut) could overcome this problem. OBJECTIVE: To obtain materials with rifampicin and isoniazid, loaded in polyelectrolyte polymers and characterize them in order to determine their utility in the development of oral delivery systems for site-specific fixeddose combination. METHODS: Carboxymethyl cellulose (CMC) and alginic acid (AA) were used as polyelectrolytes. Series of complexes CMC-rifampicin and AA-isoniazid were obtained. The type of interaction, loading capacity and rheological properties were characterized in solid materials, which after compaction under simple or combined matrixes were testedin biorrelevant media. RESULTS: The interaction between components was ionic, and loading capacity was 100%.The powders showed unfavorable flow properties, improving by granulation. Release of rifampicin in acidic medium was fast, with minimal concomitant levels of isoniazid. The selected matrix showed a controlled release of isoniazid, which was completed after 3 hours in simulated intestinal media. CONCLUSIONS: The new materials can be used for the development of site specific oral formulations of rifampicin and isoniazid. They may lead to improved effectiveness, reduced side effects and higher rifampicin stability.

Characterization of the solubility and solid-state properties of saccharin salts of fluoroquinolones.

Saccharinates salts of the fluoroquinolone antibiotics norfloxacin, ciprofloxacin, ofloxacin, and enrofloxacin were obtained as pure crystalline anhydrous solids with sweet taste. The products were characterized by one- ((13)C) and two-dimensional ((1)H-(13)C) dimensions solid state Nuclear Magnetic Resonance and infrared spectroscopy showing ionic interactions between the saccharine amide and the fluoroquinolone piperazine. Several intermolecular bindings were also identified. Thermal behavior and powder X-ray diffraction provided complementary evidences of salt formation. The series of products showed improved properties with respect to water solubility. A solubility model was developed. These salts would be a good way forward to developing more suitable formulations of these APIs.