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.

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

INTRODUCCION: El tratamiento de la tuberculosis requiere de la administración conjunta de rifampicina (RIF) e isoniacida (ISO). RIF se descompone en medio ácido al producto 3-FRSV, que en presencia de ISO forma IH. La liberación secuencial de RIF en estómago e ISO en intestino podría llevar a un incremento en la estabilidad de RIF. En una etapa previa RIF e ISO se asociaron a los polielectrolitos carboximetilcelulosa (CMC) y ácido algínico (AA), respectivamente, para obtener los materiales portadores CMC-RIF y AA-ISO que permiten la liberación inmediata de RIF y sostenida ISO. Los mismos pueden ser comprimidos para formar matrices hidrofílicas polielectrolico-fármaco (MHPF).OBJETIVO: Evaluar el impacto de la liberación secuencial de RIF e ISO en la estabilidad de RIF en condiciones simulando el contenido gástrico.METODOS: Los estudios de liberación desde las MHPF MCM-RIF + AA-ISO se realizaron en fluido gástrico simulado, utilizando referencia soluciones de RIF o RIF + ISO y la matric CMC-RIF en las mismas condiciones. La evaluación se realizó durante 2 hs, a 37ºC utilizando el aparato 2. La cuantificación se realizó mediante un método de HPLC indicativo de estabilidad, que permitió identificar ambos fármacos y sus productos de degradación.RESULTADOS: La MHPF CMC-RIF presenta muy rápida velocidad de disolución. La combinación de las MHPF CMC-RIF y AA-ISO permite la liberación selectiva e inmediata de RIF en medio ácido, con mínimos niveles concominantes de ISO, permitiendo una reducción en la formación de IH. Este producto de descomposición ha sido asociado con incremento en los eventos hepatotóxicos asociados a la combinación de RIF e ISO. Sin embargo, CMC acelera la degradación de RIF a 3-FRSV.CONCLUSIONES: La liberación secuencial de RIF e ISO permite reducir la formación de IH y es una estrategia adecuada para el desarrollo de comprimidos bi-capa. La optimización de la estabilidad requiere la adecuación de la capa de liberación inmediata de RIF.

INTRODUCTION: Tuberculosis treatment requires the administration of a combination of rifampicin (RIF) and isoniazid (ISO). In acidic media RIF decomposes to 3-FRSV, which in the presence of ISO forms IH. The sequential release of RIF in the stomach and ISO in the intestine could lead to an increase in RIF stability. In a previous work RIF and ISO were associated to the polyelectrolytes carboxymethylcellulose (CMC) and alginic acid (AA) to obtain carrier material CMC-RIF and AA-ISO that allow immediate release of RIF sustained of ISO. These materials can be compressed to form swellable drug polyelectrolyte matrices (SDPM).OBJECTIVE: To evaluate the impact of the sequential release of RIF and ISO in the stability of RIF in conditions simulating gastric contents.METHODS: Release studies were carried out from SDPM CMC-RIF + AA-ISO in simulated gastric fluid using as references RIF or RIF + ISO solutions under the same conditions. Samples were taken for 2 hs at 37ºC, using apparatus 2. The presence of both drugs and degradation products was analyzed by a stability indicating HPLC techinique.RESULTS: The SDPM CMC-RIF presented very fast release rate. The combination of SDPM CMC-RIF and AA-ISO permits selective and immediate release of RIF in acidic media, with minumum levels of ISO, with noticeable reduction of IH formation. This product has been associated with an increased frequency in hepatotoxic events associated with RIF and ISO combination. However, CMC accelerated degradation of RIF to 3-FRSV.CONCLUSIONS: Sequential release of RIF and ISO allowed a reduction in the formation of IH and seemed to be a suitable strategy for the development of bilayer tablets. Stability optimization should include adapting the immediate release layer of RIF.

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

INTRODUCCION: El tratamiento de la tuberculosis requiere de la administración conjunta de rifampicina (RIF) e isoniacida (ISO). RIF se descompone en medio ácido al producto 3-FRSV, que en presencia de ISO forma IH. La liberación secuencial de RIF en estómago e ISO en intestino podría llevar a un incremento en la estabilidad de RIF. En una etapa previa RIF e ISO se asociaron a los polielectrolitos carboximetilcelulosa (CMC) y ácido algínico (AA), respectivamente, para obtener los materiales portadores CMC-RIF y AA-ISO que permiten la liberación inmediata de RIF y sostenida ISO. Los mismos pueden ser comprimidos para formar matrices hidrofílicas polielectrolico-fármaco (MHPF).OBJETIVO: Evaluar el impacto de la liberación secuencial de RIF e ISO en la estabilidad de RIF en condiciones simulando el contenido gástrico.METODOS: Los estudios de liberación desde las MHPF MCM-RIF + AA-ISO se realizaron en fluido gástrico simulado, utilizando referencia soluciones de RIF o RIF + ISO y la matric CMC-RIF en las mismas condiciones. La evaluación se realizó durante 2 hs, a 37ºC utilizando el aparato 2. La cuantificación se realizó mediante un método de HPLC indicativo de estabilidad, que permitió identificar ambos fármacos y sus productos de degradación.RESULTADOS: La MHPF CMC-RIF presenta muy rápida velocidad de disolución. La combinación de las MHPF CMC-RIF y AA-ISO permite la liberación selectiva e inmediata de RIF en medio ácido, con mínimos niveles concominantes de ISO, permitiendo una reducción en la formación de IH. Este producto de descomposición ha sido asociado con incremento en los eventos hepatotóxicos asociados a la combinación de RIF e ISO. Sin embargo, CMC acelera la degradación de RIF a 3-FRSV.CONCLUSIONES: La liberación secuencial de RIF e ISO permite reducir la formación de IH y es una estrategia adecuada para el desarrollo de comprimidos bi-capa. La optimización de la estabilidad requiere la adecuación de la capa de liberación inmediata de RIF.

INTRODUCTION: Tuberculosis treatment requires the administration of a combination of rifampicin (RIF) and isoniazid (ISO). In acidic media RIF decomposes to 3-FRSV, which in the presence of ISO forms IH. The sequential release of RIF in the stomach and ISO in the intestine could lead to an increase in RIF stability. In a previous work RIF and ISO were associated to the polyelectrolytes carboxymethylcellulose (CMC) and alginic acid (AA) to obtain carrier material CMC-RIF and AA-ISO that allow immediate release of RIF sustained of ISO. These materials can be compressed to form swellable drug polyelectrolyte matrices (SDPM).OBJECTIVE: To evaluate the impact of the sequential release of RIF and ISO in the stability of RIF in conditions simulating gastric contents.METHODS: Release studies were carried out from SDPM CMC-RIF + AA-ISO in simulated gastric fluid using as references RIF or RIF + ISO solutions under the same conditions. Samples were taken for 2 hs at 37ºC, using apparatus 2. The presence of both drugs and degradation products was analyzed by a stability indicating HPLC techinique.RESULTS: The SDPM CMC-RIF presented very fast release rate. The combination of SDPM CMC-RIF and AA-ISO permits selective and immediate release of RIF in acidic media, with minumum levels of ISO, with noticeable reduction of IH formation. This product has been associated with an increased frequency in hepatotoxic events associated with RIF and ISO combination. However, CMC accelerated degradation of RIF to 3-FRSV.CONCLUSIONS: Sequential release of RIF and ISO allowed a reduction in the formation of IH and seemed to be a suitable strategy for the development of bilayer tablets. Stability optimization should include adapting the immediate release layer of RIF.

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.