The role of pH and dose/solubility ratio on cocrystal dissolution, drug supersaturation and precipitation.

Cocrystals that are more soluble than the constituent drug, generate supersaturation levels during dissolution and are predisposed to conversion to the less soluble drug. Drug release studies during cocrystal dissolution generally compare several cocrystals and their crystal structures. However, the influence of drug dose and solubility in different dissolution media has been scarcely reported. The present study aims to investigate how drug dose/solubility ratio (Do=Cdose/Sdrug), cocrystal solubility advantage over drug (SA=Scocrystal/Sdrug), and dissolution media affect cocrystal dissolution-drug supersaturation and precipitation (DSP) behavior. SA and Ksp values of 1:1 cocrystals of meloxicam-salicylic acid (MLX-SLC) and meloxicam-maleic acid (MLX-MLE) were determined at cocrystal/drug eutectic points. Results demonstrate that both cocrystals enhance SA by orders of magnitude (20 to 100 times for the SLC and over 300 times for the MLE cocrystal) in the pH range of 1.6 to 6.5. It is shown that during dissolution, cocrystals regulate the interfacial pH (pHint) to 1.6 for MLX-MLE and 4.5 for MLX-SLC, therefore diminishing the cocrystal dissolution rate dependence on bulk pH. Do values ranged from 2 (pH 6.5) to 410 (pH 1.6) and were mostly determined by the drug solubility dependence on pH. Drug release profiles show that maximum supersaturation (σmax=Cmax/Sdrug)and AUC increased with increasing Do as pH decreased. When Do>>SA, the cocrystal solubility is not sufficient to dissolve the dose so that a dissolution-precipitation quasi-equilibrium state is able to sustain supersaturation for the extent of the experiment (24 h). When Do<

Carbamide peroxide nanoparticles for dental whitening application: Characterization, stability and in vivo/in situ evaluation.

Carbamide peroxide is the popular home dental whitening agent. However, it has critical stability. Nanoparticles have been applied to develop products with advantages properties as better efficacy and stability increase. The aim of this study was the characterization of carbamide peroxide polymeric nanoparticles, their bleaching efficacy, effects on pulp damage and stability evaluation. Particle size demonstrated a spherical morphology and bimodal distribution (11 and 398 nm). Nanoparticles presented high entrapment efficiency (98.94%) and the zeta potential value was slightly positive (+10.26 mV). Regardless of the zeta potential, the steric effect may contribute to carbamide peroxide nanoparticle stabilization. The stability studies conducted at room temperature suggested that carbamide peroxide nanoparticles could maintain all the parameters evaluated (size, polydispersity index, zeta potential, entrapment efficiency, pH and content) for at least 90 days. Instability index was determined by dispersion analyzer (LUMiSizer ®), was 0.018, and the light transmission profile did not present sedimentation. Carbamide peroxide nanoparticles were able to prevent thermal degradation and photostability. Clinical efficacy of the whitening gels was obtained by color change in the spectrophotometer and the results showed that all the evaluated gels containing the nanoparticles (0, 1, 2 and 5% of real carbamide peroxide) were effective at bleaching after 2 h of home whitening treatment (during 30 days). After the treatment, the extracted teeth showed no in situ pulp damage by histological evaluation. The nanotechnology strategy of converting carbamide peroxide into polymeric nanoparticles revealed a new product with improved stability, a good approach for carbamide peroxide delivery.

Cocrystallization as a novel approach to enhance the transdermal administration of meloxicam.

Despite its large effectiveness, the long-term oral administration of high doses of meloxicam (MLX) may lead to gastrointestinal events such as abdominal pain, diarrhea, dyspepsia, ulceration, hemorrhage, and gastrointestinal perforation. Moreover, the pH-dependent solubility of MLX makes the development of new oral formulations even more challenging. As an alternative to overcome these limitations, the transdermal delivery of this drug has been purposed. Although various physical and chemical approaches to enhance the absorption of MLX may be found in literature, the use of cocrystallization has not been reported so far. Cutaneous permeation of MLX and 1:1 meloxicam-salicylic acid cocrystal (MLX-SLC) were evaluated using Franz diffusion cells. Cocrystal was suspended in an aqueous solution and in a gel to evaluate the vehicle effect on permeation parameters. In aqueous medium, the cocrystallization showed to enhance the drug permeation coefficient from 1.38 to 2.15 × 10-3 cm/h. MLX-SLC generated supersaturation with respect to the drug during dissolution studies simulating the conditions in the Franz cell donor chamber. This greater amount of free drug in the solution could contribute to explain the higher transdermal absorption and shorter lag time of this system. In addition, the acidic coformer ionization led to a pH reduction from 7.4 to 5.8, which, in turn, provided an increase in the unionized species of the drug, enhancing its permeation rate. The gel containing cocrystals reduced MLX permeation rate significantly (P = 0.42 × 10-3 cm/h), which was attributed to its higher viscosity.

LC/QTOF profile and preliminary stability studies of an enriched flavonoid fraction of Cecropia pachystachya Trécul leaves with potential antidepressant-like activity.

There is increasing interest in natural antioxidants that are candidates for the prevention of brain damage occurring in major depressive disorders. Cecropia pachystachya is a tropical tree species of Central and South America and a rich source of polyphenols, particularly flavonoids. The aim of this study was to characterize the flavonoid profile of an enriched flavonoid fraction of C. pachystachya (EFF-Cp) and evaluate the antidepressant-like effects of its acute administration in behavior, cytokine levels, oxidative stress and energy metabolism parameters. The EFF-Cp chemical characterization was performed by HPLC/DAD and LC/QTOF. The antidepressant-like effects were performed by the forced swimming test, splash test and open field test. EFF-Cp revealed 15 flavonoids, including seven new glycosyl flavonoids for C. pachystachya. Quantitatively, EFF-Cp showed isoorientin (43.46 mg/g), orientin (23.42 mg/g) and isovitexin (17.45 mg/g) as major C-glycosyl flavonoids. In addition, EFF-Cp at doses 50 and 100 mg/kg reduced the immobility time in the forced swimming test, without changing the locomotor activity and grooming time. In addition, EFF-Cp was able to prevent the oxidative damage in some brain areas. In conclusion, the results of this study suggest that EFF-Cp exerts antidepressant-like effects with its antioxidant properties.

Crystallization of progesterone polymorphs using polymer-induced heteronucleation (PIHn) method.

Progesterone is a natural hormone steroid used in humans for several treatments and in livestock for artificial insemination, which exhibits two polymorphic forms at ambient conditions: form 1 and form 2. Form 2 is metastable and more soluble than form 1; however, it is not suitable to use as powder raw material because it transforms into form 1 by the effects of grinding. A polymorphic screening of progesterone based on polymer-induced heteronucleation method was performed as an alternative to prepare the metastable form. Polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC), dextran, gelatin, polyisoprene (PI) and acrylonitrile-butadiene (NBR) copolymer were used. Crystals were prepared from 0.5, 10 and 40 mg/mL solutions in acetone at room temperature by solvent evaporation. The samples were characterized by X-ray powder diffraction, differential scanning calorimetry (DSC), scanning electron microcopy and attenuated total reflectance infrared Fourier transform spectroscopy. Form 1 was nucleated from 40 mg/mL solutions on the six polymers and from 10 mg/mL solutions on PI and NBR. The mixture of form 1 and form 2 was obtained from 10 mg/mL solution on HPMC, dextran and gelatin and from 0.5 mg/mL solution crystallizations. Therefore, the polymeric devices, which crystallized the metastable and more soluble polymorph (2) of progesterone, would be a promissory alternative for the pharmaceutical applications.

Dissolution properties, solid-state transformation and polymorphic crystallization: progesterone case study.

Progesterone is a natural steroid hormone and a poor soluble drug which presents two polymorphs (forms 1 and 2). Different methods to obtain form 2 were tested and a complete solid-state characterization of both polymorphs (forms 1 and 2) was conducted. X-ray powder diffraction, hot stage microscopy, Fourier transform infrared, dispersive Raman, (13)C solid-state nuclear magnetic resonance spectroscopy, thermal analysis, scanning electron microscopy techniques and intrinsic dissolution rates (IDR) were applied to investigate physical-chemical and dissolution properties of these two polymorphs. Form 2 was obtained from diluted solutions and from melting after cooling at room temperature. Form 1 was obtained from concentrated solutions and, a mixture of both polymorphs was crystallized from intermediate solutions. The crystal habit was not a distinctive characteristic of each polymorph. The effect of mechanical stress was evaluated in the metastable polymorph (form 2). We observed that grinding form 2 produced seeds of form 1 that induced the transformation of form 2 into form 1 at high temperature. The polymorphic quantification from XRD patterns of ground samples were carried out by the Rietveld method. After grinding and at room temperature conditions (∼25 °C), it was observed the transformation of 17% of form 2 into form 1 in 10 days.

Estudos dos aspectos técnicos e legais relacionados aos medicamentos e seus impactos na assistência farmacêutica

O conteúdo aborda os conceitos básicos sobre medicamentos, permitindo a diferenciação destes conceitos, bem como o entendimento da situação histórica do setor e a política farmacêutica no Brasil. O conteúdo possibilita a compreensão de que os aspectos legais relacionados aos medicamentos nunca são definitivos, e sim algo em constante movimento e revisão. Na gestão da assistência farmacêutica, os aspectos técnicos relacionados à qualidade de medicamentos são de grande relevância, contribuindo para que se adquiram medicamentos seguros, eficazes e de qualidade. A abordagem sobre a qualidade de medicamentos é bastante ampla, por isso, procurou-se destacar aqueles aspectos técnicos que podem ter um maior impacto em algumas das etapas desse processo de gestão, tais como boas práticas de fabricação, aspectos de controle de qualidade e de estabilidade e aspectos de vigilância sanitária. O conteúdo apresenta, também, o processo de construção da Política Nacional de Práticas Integrativas e Complementares (PNPIC) ­ SUS, relacionando-o com a história do uso das plantas medicinais, o seu potencial terapêutico e o seu uso como fonte de medicamentos. O conteúdo segue apresentando as resoluções sobre o registro de medicamentos fitoterápicos e seus impactos na eficácia, segurança e qualidade, por meio de uma trajetória histórica das regulamentações no Brasil e no mundo. Ao final desta Unidade, abordam-se ainda as potencialidades e os riscos da Fitoterapia no SUS e os critérios para seleção e qualificação de fornecedores de fitoterápicos.

Development and physicochemical characterization of saquinavir mesylate solid dispersions using Gelucire 44/14 or PEG 4000 as carrier.

Solid dispersions of saquinavir mesylate containing either Gelucire® 44/14 or poly(ethylene glycol) (PEG) 4000, or mixtures of each carrier with Tween 80 or polyvinyl pyrrolidone (PVP) K30 were prepared in order to enhance the drug dissolution rate. These systems were prepared by the melting method and characterized by X-ray powder diffraction, microscopical techniques, and Raman spectroscopy aiming to establish a relationship between physicochemical and dissolution properties under different cooling conditions. Modifications in degree of crystalline order/disorder over time were observed in preparations with both carriers. Overall, formulations cooled and stored at -20 °C showed less variation in dissolution rates than those at 25 °C. Although Tween 80 has enhanced the known self-emulsifying properties of Gelucire® 44/14, its combination with PEG 4000 displayed miscibility problems. The addition of PVP K30 was not the most effective approach in enhancing the dissolution in early steps; however, the drug dissolution was stable after 7 days of storage at 25 °C. The combination of PEG 4000 and PVP K30 maintained the dissolution properties for 60 and 90 days at 25 °C/95% relative humidity and 40 °C/75% (f2 values >50), respectively.

Single crystal structure, solid state characterization and dissolution rate of terbinafine hydrochloride.

Terbinafine hydrochloride (TH), a poorly water soluble antifungal agent, was characterized by solid state techniques including differential scanning calorimetry, thermogravimetry, X-ray powder diffraction, optical and electron microscopies, Fourier transform infrared, Raman and solid-state nuclear magnetic resonance spectroscopies and intrinsic dissolution rate (IDR). A colorless single crystal of TH was grown from an ethanol:water solution and its crystalline structure was determined through X-ray single crystal diffraction. Also, a new crystal habit of TH was obtained through the slow solvent evaporation technique revealing a needle-like shape. A comparison between the IDR results for the TH raw material and TH needle-like crystal revealed lower values for the new crystal habit, which can be attributed to the preferential orientation of the crystals in the compressed disks.

Gestão da Assistência Farmacêutica: módulo 2: unidade 2: estudo de aspectos técnicos relacionados aos medicamentos e seus impactos na assistência farmacêutica

Na gestão da assistência farmacêutica, os aspectos técnicos relacionados à qualidade de medicamentos são de grande relevância, contribuindo para que se adquiram medicamentos seguros, eficazes e de qualidade. A abordagem sobre a qualidade de medicamentos é bastante ampla, por isso, procurou-se destacar aqueles aspectos técnicos que podem ter um maior impacto em algumas das etapas desse processo de gestão, tais como boas práticas de fabricação, aspectos de controle de qualidade e de estabilidade e aspectos de vigilância sanitária. Ao final do material, espera-se que o aluno reconheça a importância do certificado de cumprimento das Boas Práticas de Fabricação para assegurar a qualidade de medicamentos, possibilitando ainda a realização da avaliação crítica dos laudos de controle de qualidade de medicamentos e a verificação da conformidade desses produtos quanto aos requisitos técnicos, notificando possíveis desvios de qualidade.

Abertura do módulo medicamento como insumo para a saúde

O vídeo apresenta a entrevista com o prof. Eloir Paulo Schenkel onde são abordados aspectos relacionados aos medicamentos como nomenclaturas (alopático, homeopatico, fitoterápico), produção, registro, propaganda e sua importância nas ações de saúde.

Spectrophotometric and HPLC determination of deflazacort in pharmaceutical dosage forms

Deflazacort (DFZ) is a glucocorticoid used as an anti-inflammatory and immunosuppressant drug. No official methods are available for DFZ determination in pharmaceutical formulations. The objective of this study was to develop, validate and compare spectrophotometric (UV and colorimetric) and high-performance liquid chromatography (HPLC) methods, for the quantitative determination of DFZ in tablets and oral suspension. For the UV method, ethanol was used as the solvent, with detection at 244 nm. The colorimetric method was based on the redox reaction with blue tetrazolium in alkaline medium, with detection at 524 nm. The method by HPLC was carried out using a C18 column, mobile phase consisting of acetonitrile:water (80:20, v/v) with a flow rate of 1.0 mL min-1 and detection at 244 nm. The methods proved linear (r > 0.999), precise (RSD < 5 percent) and accurate (recovery > 97 percent). Statistical analysis of the results indicated that the UV and HPLC methods were statistically equivalent, while the values obtained for the colorimetric method differed significantly from the other methods.

O deflazacorte (DFZ) é um fármaco glicocorticóide usado como antiinflamatório e imunossupressor. Métodos oficiais não estão disponíveis para a determinação de DFZ em formas farmacêuticas. Este estudo teve como objetivo desenvolver, validar e comparar métodos por espectrofotometria (UV e colorimetria) e cromatografia líquida de alta eficiência (CLAE), na determinação quantitativa de DFZ em comprimidos e suspensão oral. O método por UV utilizou etanol como solvente, com detecção em 244 nm. O método colorimétrico foi baseado na reação de redução com azul de tetrazólio em meio alcalino, com detecção em 524 nm. O método por CLAE utilizou coluna C18; fase móvel constituída de acetonitrila:água (80:20, v/v), com fluxo de 1,0 mL min-1 e detecção em 244 nm. Os métodos foram lineares (r > 0,999); precisos (RSD < 5 por cento), e exatos (recuperação > 97 por cento). As análises estatísticas dos resultados obtidos indicaram que os métodos por UV e por CLAE foram estatisticamente equivalentes, enquanto os valores obtidos para o método colorimétrico diferiram significativamente dos demais métodos.

HIV/AIDS treatment and physicochemical quality control of medicines: evaluation of non-generic lamivudine + zidovudine tablets manufactured in Brazil

In this work it was evaluated the physicochemical quality of lamivudine + zidovudine tablets, whose association belongs to the list of drugs distributed by the Brazil's National Program on Sexually Transmitted Diseases and AIDS. Four non-generic products (lamivudine + zidovudine tablets) were analyzed. They were obtained from different Brazilian manufacturers, besides a reference product. The quality was evaluated by physicochemical tests described in the official codes. A validated reversed-phase high performance liquid chromatography (HPLC) method was used for the assay of the active substances. All samples were in accordance to the requisites in relation to their physicochemical characteristics. Dissolution studies showed similar drug percentual dissolved among all samples. The results reflect the interest of the national pharmaceutical industry to ensure the delivery of safer and cheaper drugs to the Brazilian people, with particular importance in the National Program on Sexually Transmitted Diseases and AIDS.

HIV/AIDS treatment and physicochemical quality control of medicines: evaluation of non-generic lamivudine + zidovudine tablets manufactured in Brazil.

In this work it was evaluated the physicochemical quality of lamivudine + zidovudine tablets, whose association belongs to the list of drugs distributed by the Brazil's National Program on Sexually Transmitted Diseases and AIDS. Four non-generic products (lamivudine + zidovudine tablets) were analyzed. They were obtained from different Brazilian manufacturers, besides a reference product. The quality was evaluated by physicochemical tests described in the official codes. A validated reversed-phase high performance liquid chromatography (HPLC) method was used for the assay of the active substances. All samples were in accordance to the requisites in relation to their physicochemical characteristics. Dissolution studies showed similar drug percentual dissolved among all samples. The results reflect the interest of the national pharmaceutical industry to ensure the delivery of safer and cheaper drugs to the Brazilian people, with particular importance in the National Program on Sexually Transmitted Diseases and AIDS.

Determination of amlodipine in pharmaceutical dosage forms by liquid chromatography and ultraviolet spectrophotometry.

A liquid chromatography (LC) method and an ultraviolet (UV) spectrophotometric method were developed and validated for quantitative determination of amlodipine in tablets and compounded capsules. The isocratic LC analyses were performed on an RP18 column using a mobile phase composed of 0.1% (v/v) ortho-phosphoric acid (pH 3.0) -acetonitrile (60 + 40, v/v) at a flow rate of 1.0 mL/min. The UV spectrophotometric method was performed at 238 nm. The analytical methods were validated according to International Conference on Harmonization Guidelines. The calibration graphs were linear [correlation coefficient (r) > 0.999] in the studied concentration range of 10-30 microg/mL for LC and 10-35 microg/mL for UV spectrophotometry. The relative standard deviation values for intraday and interday precision studies were less than 2%, and the accuracy was greater than 98% for both methods. The specificity of the LC method was proved using forced degradation. Statistical analyses showed no significant difference between the results obtained by the 2 methods. The proposed methods are precise and accurate and can be applied directly and easily to the oral pharmaceutical preparations of amlodipine.

Spectrophotometric determination of oxiconazole in topical lotion using methyl orange.

A spectrophotometric method is described for the determination of oxiconazole in raw material and in topical lotion. This method is based on the reaction of the oxiconazole with methyl orange in buffered aqueous solution of citric acid at pH 2.3. The chromogen, being extractable with dichloromethane, could be measured quantitatively with maximum absorption at 427 nm. The Lambert-Beer law was obeyed in the concentration range of 4.0-14.0 microg ml(-1). A prospective validation of the method showed that the method was linear (r=0.9995), precise (intra-day: CV=1.57% and inter-day: CV=1.50%) and accurate (mean recoveries: 99.69%). The results compared favourably with those of the HPLC method.

Validation of UV spectrophotometric and nonaqueous titration methods for the determination of carvedilol in pharmaceutical formulations.

Ultraviolet (UV) spectrophotometric and nonaqueous volumetric methods are described for the determination of carvedilol in pharmaceutical formulations. Linearity, precision, and accuracy were evaluated according to the validation guidelines of the International Conference on Harmonization and the United States Pharmacopeia for both methods. The UV spectrophotometric procedure was performed in ethanol at 244 nm. Good linearity was obtained between 2 and 7 microg/mL with a correlation coefficient of 0.9999. The intra- and interday precision values were <2% for all samples analyzed. The accuracy, determined from recovery studies, was between 97.5 and 102.2%. The other procedure was based on the volumetric quantitation of carvedilol in a nonaqueous medium with 0.01 M perchloric acid and 1% violet crystal as the indicator. The validation of the volumetric method yielded good results that included linearity (r of > 0.999), precision (relative standard deviations of <2% for intra- and interday precision), and accuracy (96.4-102.4%). The methods were applied to tablets and compounded capsules. Statistical analysis by analysis of variance showed no significant difference between the results obtained by the proposed methods.

LC method for the analysis of Oxiconazole in pharmaceutical formulations.

A LC method has been developed for the quantitative determination of Oxiconazole (Ox) in bulk form, lotion and cream pharmaceutical formulations. The method validation yielded good results including the range, linearity, precision, accuracy, recovery, specificity, robustness, limit of quantitation and limit of detection. The LC separation was carried by reversed phase chromatography using a LiChrocart C(8) column (125 mm x 4.0 mm i.d., 5 microm particle size). The mobile phase was composed of methanol-0.02 M ammonium acetate buffer (85:15 v/v), pumped isocratically at flow rate 1 ml min(-1). The detection was carried out on UV detector at 254 nm. The calibration curve for Ox was linear from 40.0-140.0 microg ml(-1) range. The precision of this method, calculated as the relative standard deviation (R.S.D.) was 1.57% for lotion and 0.71% for cream. The R.S.D. values for intra- and inter-day precision studies were 0.57 and 1.34%, respectively. The recovery of the drug ranged between 98.84-102.2% (lotion) and 100.54-101.59% (cream). The stability indicating capability of the assays was proved using forced degradation. Chromatograms showed Ox well resolved from the degradation product.