A indústria farmacêutica tem como principal objetivo planejar, sintetizar e caracterizar compostos químicos que possuam atividade biológica e que sejam úteis no controle e combate de doenças e sintomas que acometem as populações. Estes compostos são referidos como ingredientes farmacêuticos ativos e podem, no estado sólido, apresentar diferentes arranjos de suas moléculas dentro de um cristal (polimorfismo). A cada um desses arranjos estão associadas propriedades físico-químicas que são de fundamental importância para o efeito terapêutico dos fármacos. Nesse contexto, este estudo teve como objetivo caracterizar as propriedades de estado sólido de novas formas cristalinas de três compostos farmacêuticos, Clorpropamida (CPA), Nevirapina (NVP) e Dietilcarbamazina (DEC). A CPA trata-se de um hipoglicemiante oral, utilizado no tratamento da Diabetes mellitus tipo II, apresentando na literatura cinco polimorfos conformacionais, dos quais dois foram caracterizados nesse estudo: as Formas IV e VI. A Forma IV cristaliza-se grupo espacial não centrossimétrico monoclínico P21, com Z = 2 e a Forma VI no grupo espacial centrossimétrico ortorrômbico Pbca, com Z = 8. Ambas apresentaram o mesmo padrão de interações intermoleculares clássicas, sendo que a principal diferença entre elas reside nas interações intermoleculares não clássicas, que levam a diferentes empacotamentos cristalinos. Por fim, as conformações moleculares dos cinco polimorfos da CPA foram comparadas entre si e as informações foram racionalizadas tomando como base os resultados provenientes de cálculos teóricos, que também indicaram a possibilidade de existência de novos polimorfos. A NVP, fármaco antiretroviral não nucleosídeo utilizado no tratamento da AIDS, também apresenta casos de polimorfismo na literatura. Neste trabalho, obteve-se um solvato não estequiométrico de butanol desse composto, que cristaliza no grupo espacial centrossimétrico triclínico P-1, com Z = 2, no qual as moléculas de butanol acomodaram-se em canais infinitos rodeados por moléculas de NVP. Esse tipo de empacotamento cristalino, diferente do reportado na literatura até o presente momento, possibilitou-nos propor que novos solvatos poderiam ser obtidos variando-se o solvente, proposta tal confirmada posteriormente. A DEC é amplamente utilizada na forma de um sal de citrato no tratamento da filariose linfática, não apresentado na literatura nenhuma caracterização de estado sólido. Assim, caracterizou-se não somente o sal utilizado nas formulações (DEC citrato), como também o composto puro (DEC). A forma pura, instável à temperatura ambiente, cristaliza no grupo espacial centrossimétrico P21/n à 250K. O sal, preferido como API por sua estabilidade, cristaliza à temperatura ambiente no grupo P21/c, porém com presença de desordem nas cadeias etílicas das moléculas de DEC. Para reduzir essa desordem, efetuou-se um estudo em função da temperatura, que acabou revelando a presença de três transições de fase sólido-sólido, gerando quatro fases cristalinas diferentes. Duas das transições exibiram efeito de histerese de acordo com a direção da rampa de temperatura. A terceira transição só foi obtida por resfriamento rápido do sistema. Estes dados foram comparados com os obtidos por DSC e espectroscopia Raman / One of the main goals of the pharmaceutical industry is to plan, synthesize and characterize chemical compounds with biological activity that can be useful in controlling diseases and symptoms that affect populations. These compounds are referred to as active pharmaceutical ingredients and may, in the solid state, present different crystal arrangements of its molecules (polymorphism). To each one of these crystalline arrays are associated physicochemical properties that are of fundamental importance for the therapeutic effect of the pharmaceutical drugs. In this context, the focus of this study was to characterize the solid state properties of new crystalline forms of three pharmaceutical compounds, Chlorpropamide (CPA), Nevirapine (NVP) and Diethylcarbamazine (DEC). CPA is an oral hypoglicemiant used in the treatment of type II Diabetes mellitus, and presents five conformational polymorphs reported in the literature, two of which were characterized in this study: Forms IV and VI. Form IV crystallizes in the monoclinic non-centrosymmetric space group P21, with Z = 2 and the Form VI in the orthorrombic centrosymmetric space group Pbca, with Z = 8. Both exhibited the same classical intermolecular interaction pattern; the main difference between them lay in the non-classical intermolecular interactions, which leads to different crystal packing. Finally, the molecular conformations of the five polymorphs of CPA were compared to each other and the information was rationalized taking as basis the results from theoretical calculations, which also indicated the possible existence of new polymorphs. NVP, a non-nucleoside antiretroviral pharmaceutical compound used in the treatment of AIDS, also presents polymorphism cases reported in the literature. In this study, we obtained a non-stoichiometric buthanol solvate of this compound, which crystallizes in the triclinic centrosymmetric space group P-1, with Z = 2, in which the buthanol molecules are positioned in infinite channels surrounded by NVP molecules. This kind of crystal packing, which is different from the one reported in the literature until now, has allowed us to propose that new solvates could be obtained by varying the solvent, being this proposal subsequently confirmed. DEC is largely used as a citrate salt form in the treatment of the lymphatic filariasis, not having any solid state characterization in the literature. Thus, we characterized not just the salt (DEC citrate) used in the formulation, but also the pure compound (DEC). The pure form, unstable at room temperature, crystallizes in the monoclinic centrosymmetric space group P21/n at 250K. The salt, preferred as API because of its stability, crystallizes at room temperature in the monoclinic centrosymmetric space group P21/c, but with the presence of disorder in the ethyl chains of the DEC molecules. To reduce this disorder, we performed a study in function of temperature, which revealed the presence of three solid-solid structural phase transitions, generating four different crystalline phases. Two of these transitions showed a hysteresis effect according to the direction of the temperature ramp. The third transition was only obtained by fast cooling of the system. These data where compared with the ones obtained by DSC and Raman spectroscopy.

A indústria farmacêutica tem como principal objetivo planejar, sintetizar e caracterizar compostos químicos que possuam atividade biológica e que sejam úteis no controle e combate de doenças e sintomas que acometem as populações. Estes compostos são referidos como ingredientes farmacêuticos ativos e podem, no estado sólido, apresentar diferentes arranjos de suas moléculas dentro de um cristal (polimorfismo). A cada um desses arranjos estão associadas propriedades físico-químicas que são de fundamental importância para o efeito terapêutico dos fármacos. Nesse contexto, este estudo teve como objetivo caracterizar as propriedades de estado sólido de novas formas cristalinas de três compostos farmacêuticos, Clorpropamida (CPA), Nevirapina (NVP) e Dietilcarbamazina (DEC). A CPA trata-se de um hipoglicemiante oral, utilizado no tratamento da Diabetes mellitus tipo II, apresentando na literatura cinco polimorfos conformacionais, dos quais dois foram caracterizados nesse estudo: as Formas IV e VI. A Forma IV cristaliza-se grupo espacial não centrossimétrico monoclínico P21, com Z = 2 e a Forma VI no grupo espacial centrossimétrico ortorrômbico Pbca, com Z = 8. Ambas apresentaram o mesmo padrão de interações intermoleculares clássicas, sendo que a principal diferença entre elas reside nas interações intermoleculares não clássicas, que levam a diferentes empacotamentos cristalinos. Por fim, as conformações moleculares dos cinco polimorfos da CPA foram comparadas entre si e as informações foram racionalizadas tomando como base os resultados provenientes de cálculos teóricos, que também indicaram a possibilidade de existência de novos polimorfos. A NVP, fármaco antiretroviral não nucleosídeo utilizado no tratamento da AIDS, também apresenta casos de polimorfismo na literatura. Neste trabalho, obteve-se um solvato não estequiométrico de butanol desse composto, que cristaliza no grupo espacial centrossimétrico triclínico P-1, com Z = 2, no qual as moléculas de butanol acomodaram-se em canais infinitos rodeados por moléculas de NVP. Esse tipo de empacotamento cristalino, diferente do reportado na literatura até o presente momento, possibilitou-nos propor que novos solvatos poderiam ser obtidos variando-se o solvente, proposta tal confirmada posteriormente. A DEC é amplamente utilizada na forma de um sal de citrato no tratamento da filariose linfática, não apresentado na literatura nenhuma caracterização de estado sólido. Assim, caracterizou-se não somente o sal utilizado nas formulações (DEC citrato), como também o composto puro (DEC). A forma pura, instável à temperatura ambiente, cristaliza no grupo espacial centrossimétrico P21/n à 250K. O sal, preferido como API por sua estabilidade, cristaliza à temperatura ambiente no grupo P21/c, porém com presença de desordem nas cadeias etílicas das moléculas de DEC. Para reduzir essa desordem, efetuou-se um estudo em função da temperatura, que acabou revelando a presença de três transições de fase sólido-sólido, gerando quatro fases cristalinas diferentes. Duas das transições exibiram efeito de histerese de acordo com a direção da rampa de temperatura. A terceira transição só foi obtida por resfriamento rápido do sistema. Estes dados foram comparados com os obtidos por DSC e espectroscopia Raman / One of the main goals of the pharmaceutical industry is to plan, synthesize and characterize chemical compounds with biological activity that can be useful in controlling diseases and symptoms that affect populations. These compounds are referred to as active pharmaceutical ingredients and may, in the solid state, present different crystal arrangements of its molecules (polymorphism). To each one of these crystalline arrays are associated physicochemical properties that are of fundamental importance for the therapeutic effect of the pharmaceutical drugs. In this context, the focus of this study was to characterize the solid state properties of new crystalline forms of three pharmaceutical compounds, Chlorpropamide (CPA), Nevirapine (NVP) and Diethylcarbamazine (DEC). CPA is an oral hypoglicemiant used in the treatment of type II Diabetes mellitus, and presents five conformational polymorphs reported in the literature, two of which were characterized in this study: Forms IV and VI. Form IV crystallizes in the monoclinic non-centrosymmetric space group P21, with Z = 2 and the Form VI in the orthorrombic centrosymmetric space group Pbca, with Z = 8. Both exhibited the same classical intermolecular interaction pattern; the main difference between them lay in the non-classical intermolecular interactions, which leads to different crystal packing. Finally, the molecular conformations of the five polymorphs of CPA were compared to each other and the information was rationalized taking as basis the results from theoretical calculations, which also indicated the possible existence of new polymorphs. NVP, a non-nucleoside antiretroviral pharmaceutical compound used in the treatment of AIDS, also presents polymorphism cases reported in the literature. In this study, we obtained a non-stoichiometric buthanol solvate of this compound, which crystallizes in the triclinic centrosymmetric space group P-1, with Z = 2, in which the buthanol molecules are positioned in infinite channels surrounded by NVP molecules. This kind of crystal packing, which is different from the one reported in the literature until now, has allowed us to propose that new solvates could be obtained by varying the solvent, being this proposal subsequently confirmed. DEC is largely used as a citrate salt form in the treatment of the lymphatic filariasis, not having any solid state characterization in the literature. Thus, we characterized not just the salt (DEC citrate) used in the formulation, but also the pure compound (DEC). The pure form, unstable at room temperature, crystallizes in the monoclinic centrosymmetric space group P21/n at 250K. The salt, preferred as API because of its stability, crystallizes at room temperature in the monoclinic centrosymmetric space group P21/c, but with the presence of disorder in the ethyl chains of the DEC molecules. To reduce this disorder, we performed a study in function of temperature, which revealed the presence of three solid-solid structural phase transitions, generating four different crystalline phases. Two of these transitions showed a hysteresis effect according to the direction of the temperature ramp. The third transition was only obtained by fast cooling of the system. These data where compared with the ones obtained by DSC and Raman spectroscopy.

CAETANO, Márcia de Windson Costa. Polimorfismo da Clorpropamida investigado através de Espectroscopia Vibracional. 2006. 141 f. Dissertação (Mestrado em Física) - Programa de Pós-Graduação em Física, Departamento de Física, Centro de Ciências, Universidade Federal do Ceará, Fortaleza, 2006. / Submitted by Edvander Pires (edvanderpires@gmail.com) on 2015-05-21T22:22:40Z No. of bitstreams: 1 2006_dis_mwccaetano.pdf: 3508898 bytes, checksum: d30348bd90f71bc8902edd696cad9095 (MD5) / Approved for entry into archive by Edvander Pires(edvanderpires@gmail.com) on 2015-05-22T19:39:13Z (GMT) No. of bitstreams: 1 2006_dis_mwccaetano.pdf: 3508898 bytes, checksum: d30348bd90f71bc8902edd696cad9095 (MD5) / Made available in DSpace on 2015-05-22T19:39:13Z (GMT). No. of bitstreams: 1 2006_dis_mwccaetano.pdf: 3508898 bytes, checksum: d30348bd90f71bc8902edd696cad9095 (MD5) Previous issue date: 2006 / Chlorpropamide (C10H13ClN2O3S, (1-[4-chlorobenzenesulphonyl]-3-propyl urea)) is a drug used to treat type II diabetes (non-dependent of insulin), especially when the diabetes can not be controlled by alimentary regimes. The polymorphism of this drug is widely documented exhibiting at least five crystalline forms. In this work, we present a vibrational study of four of these polymorphs by using Raman, infrared and near-infrared spectroscopies. The objective of this vibrational investigation is to correlate the vibrational modes with the possible crystalline structures, as well as, to evaluate these methods as a tool for identification and quality control of raw materials and formulated products. In order to provide a detailed characterization we also applied thermal analyses and x-ray powder diffraction techniques to identify the crystalline forms. Finally, the assignment of the bands observed in the vibrational spectra in terms of the normal vibrational modes was performed with the help the quantum mechanical calculations based on the density functional theory. These results allow us to investigate the conformational stability of chlorpropamide establishing correlations with the polymorphism of this drug. / A clorpropamida (C10H13ClN2O3S, (1-[4-chlorobenzenesulphonyl]-3-propyl urea)) é uma droga usada para tratar o diabetes tipo II (não dependente da insulina), em particular em pessoas cujo diabetes não pode ser controlada só pelo regime alimentício. O polimorfismo desta droga se encontra amplamente documentado exibindo, pelo menos, cinco diferentes formas cristalinas. Neste trabalho apresentamos um estudo de quatro destes polimorfos através das espectroscopias Raman, infravermelho e infravermelho próximo. O objetivo desta investigação vibracional é estabelecer correlações entre os modos vibracionais e as possíveis estruturas cristalinas, além de avaliar estes métodos como ferramentas para a identificação e controle de qualidade das matérias primas e produtos formulados. No intuito de prover uma caracterização detalhada também empregamos análises térmicas e difração de raios- X para a identificação prévia das formas cristalinas. Finalmente, a classificação das bandas observadas nos espectros vibracionais em termos dos modos normais de vibração da molécula foi realizada com a ajuda de cálculos computacionais baseados na teoria do funcional de densidade. Estes resultados também nos permitiram investigar a estabilidade conformacional da clorpropamida e estabelecer correlações com o polimorfismo da mesma.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A clorpropamida (C10H13ClN2O3S, (1-[4-chlorobenzenesulphonyl]-3-propyl urea)) à uma droga usada para tratar o diabetes tipo II (nÃo dependente da insulina), em particular em pessoas cujo diabetes nÃo pode ser controlada sà pelo regime alimentÃcio. O polimorfismo desta droga se encontra amplamente documentado exibindo, pelo menos, cinco diferentes formas cristalinas. Neste trabalho apresentamos um estudo de quatro destes polimorfos atravÃs das espectroscopias Raman, infravermelho e infravermelho prÃximo. O objetivo desta investigaÃÃo vibracional à estabelecer correlaÃÃes entre os modos vibracionais e as possÃveis estruturas cristalinas, alÃm de avaliar estes mÃtodos como ferramentas para a identificaÃÃo e controle de qualidade das matÃrias primas e produtos formulados. No intuito de prover uma caracterizaÃÃo detalhada tambÃm empregamos anÃlises tÃrmicas e difraÃÃo de raios- X para a identificaÃÃo prÃvia das formas cristalinas. Finalmente, a classificaÃÃo das bandas observadas nos espectros vibracionais em termos dos modos normais de vibraÃÃo da molÃcula foi realizada com a ajuda de cÃlculos computacionais baseados na teoria do funcional de densidade. Estes resultados tambÃm nos permitiram investigar a estabilidade conformacional da clorpropamida e estabelecer correlaÃÃes com o polimorfismo da mesma. / Chlorpropamide (C10H13ClN2O3S, (1-[4-chlorobenzenesulphonyl]-3-propyl urea)) is a drug used to treat type II diabetes (non-dependent of insulin), especially when the diabetes can not be controlled by alimentary regimes. The polymorphism of this drug is widely documented exhibiting at least five crystalline forms. In this work, we present a vibrational study of four of these polymorphs by using Raman, infrared and near-infrared spectroscopies. The objective of this vibrational investigation is to correlate the vibrational modes with the possible crystalline structures, as well as, to evaluate these methods as a tool for identification and quality control of raw materials and formulated products. In order to provide a detailed characterization we also applied thermal analyses and x-ray powder diffraction techniques to identify the crystalline forms. Finally, the assignment of the bands observed in the vibrational spectra in terms of the normal vibrational modes was performed with the help the quantum mechanical calculations based on the density functional theory. These results allow us to investigate the conformational stability of chlorpropamide establishing correlations with the polymorphism of this drug.

Applications of Hot Melt Extrusion (HME) in pharmaceuticals have become increasingly popular over the years but nonetheless a few obstacles still remain before wide scale implementation. In many instances these improvements are related to both processing and product performance. It is observed that HME process optimisation is majorly focused on the active pharmaceutical ingredient's (API) properties. Characterising polymeric properties for their suitability in HME should be equally studied since the impact of excipients on both product and process performance is just as vital. In this work, two well-established cellulose ester derivatives: Hydroxy Propyl Methyl Cellulose Acetate Succinate (HPMCAS) and Hydroxy Propyl Methyl Cellulose Phthalate (HPMCP) are studied for their HME suitability. Their thermal, thermodynamic, rheological, thermo-chemical and degradation kinetic properties were evaluated with model plasticisers and APIs. It was found the thermal properties of HPMCP are severely compromised whereas HPMCAS is more stable in the processing zone of 150 to 200 °C. Thermodynamic properties revealed that both polymers share an important solubility parameter range (20-30 MPa P1/2P) where the majority of plasticisers and BCS class II APIs lie. Thus, greater miscibility/solubility can be expected. Further, the processability of these two polymers investigated by rheometric measurements showed HPMCAS possesses better flow properties than HPMCP because HPMCP forms a weak network of chain interactions at a molecular level. However, adding plasticisers such as PEG and TEC the flow properties of HPMCP can be tailored. The study also showed that plasticisers have a major influence on thermo-chemical and kinetic properties of polymers. For instance, PEG reduced polymer degradation with reversal in kinetic parameters whereas blends of CA produced detrimental effects and increased polymer degradation with reduction in onset degradation temperatures. Further, both polymers are observed to be chemically reactive with the APIs containing free -OH, -SOR2RN- and -NH2 groups. Finally, these properties prove that suitability of HPMCP is highly debated for HME and demands great care in use while that of HPMCAS is relatively better than HPMCP in many instances.

Applications of Hot Melt Extrusion (HME) in pharmaceuticals have become increasingly popular over the years but nonetheless a few obstacles still remain before wide scale implementation. In many instances these improvements are related to both processing and product performance. It is observed that HME process optimisation is majorly focused on the active pharmaceutical ingredient's (API) properties. Characterising polymeric properties for their suitability in HME should be equally studied since the impact of excipients on both product and process performance is just as vital. In this work, two well-established cellulose ester derivatives: Hydroxy Propyl Methyl Cellulose Acetate Succinate (HPMCAS) and Hydroxy Propyl Methyl Cellulose Phthalate (HPMCP) are studied for their HME suitability. Their thermal, thermodynamic, rheological, thermo-chemical and degradation kinetic properties were evaluated with model plasticisers and APIs. It was found the thermal properties of HPMCP are severely compromised whereas HPMCAS is more stable in the processing zone of 150 to 200 °C. Thermodynamic properties revealed that both polymers share an important solubility parameter range (20-30 MPa P1/2P) where the majority of plasticisers and BCS class II APIs lie. Thus, greater miscibility/solubility can be expected. Further, the processability of these two polymers investigated by rheometric measurements showed HPMCAS possesses better flow properties than HPMCP because HPMCP forms a weak network of chain interactions at a molecular level. However, adding plasticisers such as PEG and TEC the flow properties of HPMCP can be tailored. The study also showed that plasticisers have a major influence on thermo-chemical and kinetic properties of polymers. For instance, PEG reduced polymer degradation with reversal in kinetic parameters whereas blends of CA produced detrimental effects and increased polymer degradation with reduction in onset degradation temperatures. Further, both polymers are observed to be chemically reactive with the APIs containing free -OH, -SOR2RN- and -NH2 groups. Finally, these properties prove that suitability of HPMCP is highly debated for HME and demands great care in use while that of HPMCAS is relatively better than HPMCP in many instances.