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1.
AAPS J ; 21(3): 44, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30915582

RESUMO

Biologic products encounter various types of interfacial stress during development, manufacturing, and clinical administration. When proteins come in contact with vapor-liquid, solid-liquid, and liquid-liquid surfaces, these interfaces can significantly impact the protein drug product quality attributes, including formation of visible particles, subvisible particles, or soluble aggregates, or changes in target protein concentration due to adsorption of the molecule to various interfaces. Protein aggregation at interfaces is often accompanied by changes in conformation, as proteins modify their higher order structure in response to interfacial stresses such as hydrophobicity, charge, and mechanical stress. Formation of aggregates may elicit immunogenicity concerns; therefore, it is important to minimize opportunities for aggregation by performing a systematic evaluation of interfacial stress throughout the product development cycle and to develop appropriate mitigation strategies. The purpose of this white paper is to provide an understanding of protein interfacial stability, explore methods to understand interfacial behavior of proteins, then describe current industry approaches to address interfacial stability concerns. Specifically, we will discuss interfacial stresses to which proteins are exposed from drug substance manufacture through clinical administration, as well as the analytical techniques used to evaluate the resulting impact on the stability of the protein. A high-level mechanistic understanding of the relationship between interfacial stress and aggregation will be introduced, as well as some novel techniques for measuring and better understanding the interfacial behavior of proteins. Finally, some best practices in the evaluation and minimization of interfacial stress will be recommended.


Assuntos
Produtos Biológicos/química , Desenvolvimento de Medicamentos , Produtos Biológicos/administração & dosagem , Química Farmacêutica , Humanos , Interações Hidrofóbicas e Hidrofílicas , Transição de Fase , Agregados Proteicos , Estabilidade Proteica , Propriedades de Superfície , Água/química
3.
Eur J Pharm Biopharm ; 120: 1-8, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28754261

RESUMO

Liquid-liquid phase separation (LLPS) has long been observed during the physical stability investigation of therapeutic protein formulations. The buffer conditions and the presence of various excipients are thought to play important roles in the formulation development of monoclonal antibodies (mAbs). In this study, the effects of several small-molecule excipients (histidine, alanine, glycine, sodium phosphate, sodium chloride, sorbitol and sucrose) with diverse physical-chemical properties on LLPS of a model IgG1 (JM2) solutions were investigated by multiple techniques, including UV-vis spectroscopy, circular dichroism, differential scanning calorimetry/fluorimetry, size exclusion chromatography and dynamic light scattering. The LLPS of JM2 was confirmed to be a thermodynamic equilibrium process with no structural changes or irreversible aggregation of proteins. Phase diagrams of various JM2 formulations were constructed, suggesting that the phase behavior of JM2 was dependent on the solution pH, ionic strength and the presence of other excipients such as glycine, alanine, sorbitol and sucrose. Furthermore, we demonstrated that for this mAb, the interaction parameter (kD) determined at low protein concentration appeared to be a good predictor for the occurrence of LLPS at high concentration.


Assuntos
Anticorpos Monoclonais/química , Excipientes/química , Soluções Farmacêuticas/química , Mapas de Interação de Proteínas/fisiologia , Proteínas/química , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Dicroísmo Circular/métodos , Concentração de Íons de Hidrogênio , Extração Líquido-Líquido/métodos , Concentração Osmolar , Bibliotecas de Moléculas Pequenas/química , Termodinâmica , Raios Ultravioleta
4.
Eur J Pharm Biopharm ; 114: 263-277, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28189625

RESUMO

Surfactants are widely used as stabilizers in the biopharmaceutical formulations to minimize protein aggregation. Under a fixed stress condition, the protecting and destabilizing effects of surfactants are hypothesized to be highly dependent on the species and concentrations of surfactants and mAb. Therefore, we here studied the aggregation-prevention and structure-perturbation effects of eight commonly used surfactants (Tw20, Tw80, Brij35, Chaps, TrX-100, SDS, Pluronic F68 and F127) on two IgG1 solution formulations under agitation, using analytical methodologies including visual inspection, OD350 measurement, HPLC-SEC, circular dicroism, fluorescence spectroscopy and differential scanning calorimetry. We found that: (1) With concentrations range from 0.02 to 2mg/mL, nonionic surfactants were found to offer efficient aggregation-prevention effect, which is superior than the ionic surfactants; and higher surfactant concentration prevented mAb aggregation better especially under prolonged stability test under stress conditions. (2) The surfactant induced structure-perturbation emerged when even higher surfactant concentration (≥2mg/mL) was used, and such effect was surfactant-property dependent; and (3) the two IgG1 demonstrated different aggregation mechanisms and surfactant dependency, especially at high mAb concentrations. In conclusion, surfactants usage in mAb formulations, including the types and concentrations, should strike an optimal balance between the desirable aggregation-prevention and the detrimental structure-perturbation effects, while the consideration of mAb aggregation mechanism and concentration is also required for surfactant assessment.


Assuntos
Anticorpos Monoclonais/química , Imunoglobulina G/química , Tensoativos/química , Composição de Medicamentos , Excipientes , Humanos , Indicadores e Reagentes , Soluções Farmacêuticas
5.
Mol Pharm ; 12(12): 4478-87, 2015 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-26528726

RESUMO

Monoclonal antibodies display complicated solution properties in highly concentrated (>100 mg/mL) formulations, such as high viscosity, high aggregation propensity, and low stability, among others, originating from protein-protein interactions within the colloidal protein solution. These properties severely hinder the successful development of high-concentration mAb solution for subcutaneous injection. We hereby investigated the effects of several small-molecule excipients with diverse biophysical-chemical properties on the viscosity, aggregation propensity, and stability on two model IgG1 (JM1 and JM2) mAb formulations. These excipients include nine amino acids or their salt forms (Ala, Pro, Val, Gly, Ser, HisHCl, LysHCl, ArgHCl, and NaGlu), four representative salts (NaCl, NaAc, Na2SO4, and NH4Cl), and two chaotropic reagents (urea and GdnHCl). With only salts or amino acids in their salt-forms, significant decrease in viscosity was observed for JM1 (by up to 30-40%) and JM2 (by up to 50-80%) formulations, suggesting charge-charge interaction between the mAbs dictates the high viscosity of these mAbs formulations. Most of these viscosity-lowering excipients did not induce substantial protein aggregation or changes in the secondary structure of the mAbs, as evidenced by HPLC-SEC, DSC, and FT-IR analysis, even in the absence of common protein stabilizers such as sugars and surfactants. Therefore, amino acids in their salt-forms and several common salts, such as ArgHCl, HisHCl, LysHCl, NaCl, Na2SO4, and NaAc, could potentially serve as viscosity-lowering excipients during high-concentration mAb formulation development.


Assuntos
Aminoácidos/química , Anticorpos Monoclonais/química , Imunoglobulina G/química , Soluções Farmacêuticas/química , Sais/química , Química Farmacêutica/métodos , Excipientes/química , Viscosidade
7.
Acta Pharm Sin B ; 4(1): 18-25, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26579360

RESUMO

The solid dispersion has become an established solubilization technology for poorly water soluble drugs. Since a solid dispersion is basically a drug-polymer two-component system, the drug-polymer interaction is the determining factor in its design and performance. In this review, we summarize our current understanding of solid dispersions both in the solid state and in dissolution, emphasizing the fundamental aspects of this important technology.

8.
Int J Pharm ; 457(1): 63-70, 2013 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-24004566

RESUMO

BCS class III hydrophilic compounds are often associated with low oral bioavailability due to their poor epithelial permeability in the gastrointestinal tract. In this study, we reported an approach of incorporating a drug complex into an in situ gelling muco-adhesive carrier to achieve an improved bioavailability of a poorly absorbed hydrophilic compound. A new molecular entity (RWJ-445167) from Johnson and Johnson was used as a model compound. The compound was first complexed with sodium lauryl sulfate (SLS). The complex was then incorporated into an in situ gelling muco-adhesive carrier Cremophor for formulation characterization and rat pharmacokinetic (PK) studies. The study results showed that RWJ-445167 bound to SLS at a stoichiometric ratio. By complexing with SLS, the compound became lipophilic. The aqueous solubility of RWJ-445167 dropped to 0.58 mg/mL for the complex from 61 mg/mL for the free compound, while the partitioning coefficient of the complex increased to 7.59, compared with 0.05 of the free compound. In the rat PK study, with duodenal administration, the complex in the in situ-gelling formulation achieved 28.24% of bioavailability, compared to 4.26% of the free compound solution. The enhanced bioavailability was also significantly higher than those in the RWJ-445167/SLS physical mixture in Cremophor (14.91%), the complex in non-gelling carrier PEG 400 (9.95%) and the RWJ-445167/SLS physical mixture in PEG 400 carrier (8.60%). The study demonstrates that incorporation of a drug complex into an in situ gelling formulation provides a new approach to improving bioavailability of BCS class III drugs.


Assuntos
Portadores de Fármacos/farmacocinética , Guanidinas/farmacocinética , Sulfonamidas/farmacocinética , Absorção , Animais , Disponibilidade Biológica , Química Farmacêutica , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Feminino , Géis , Glicerol/análogos & derivados , Glicerol/química , Guanidinas/administração & dosagem , Guanidinas/química , Interações Hidrofóbicas e Hidrofílicas , Masculino , Ratos , Ratos Sprague-Dawley , Dodecilsulfato de Sódio/química , Sulfonamidas/administração & dosagem , Sulfonamidas/química
9.
Int J Pharm ; 453(1): 36-43, 2013 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-23680727

RESUMO

Use of supersaturable formulations has been demonstrated as an effective approach to improve solubility and oral absorption of poorly water-soluble compounds. In supersaturable formulations, drug concentration exceeds the equilibrium solubility when the formulations are exposed to the gastrointestinal fluids and drug might precipitate before being absorbed, resulting in delayed response, and reduced efficacy or compromised bioavailability. Polymer based drug precipitation inhibitors have been used to inhibit or retard such precipitation. In this manner one can maintain a drug in the supersaturated concentration for an extended period of time, leading to significantly improved bioavailability of the poorly water-soluble drugs. This review article discusses different types of precipitation inhibitors, working hypotheses, and case studies with improved oral bioavailability.


Assuntos
Precipitação Química , Preparações Farmacêuticas/química , Química Farmacêutica , Ciclodextrinas/química , Polímeros/química , Solubilidade , Tensoativos/química
10.
Mol Pharm ; 9(5): 1100-8, 2012 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-22376012

RESUMO

Poorly water-soluble weakly basic compounds which are solubilized in gastric fluid are likely to precipitate after the solution empties from the stomach into the small intestine, leading to a low oral bioavailability. In this study, we reported an approach of combining solubilization agents and precipitation inhibitors to produce a supersaturated drug concentration and to prolong such a drug concentration for an extended period of time for an optimal absorption, thereby improving oral bioavailability of poorly water-soluble drugs. A weakly basic compound from Johnson and Johnson Pharmaceutical Research and Development was used as a model compound. A parallel microscreening precipitation method using 96-well plates and a TECAN robot was used to assess the precipitation of the tested compound in the simulated gastric fluid (SGF) and the simulated intestinal fluid (SIF), respectively, for lead solubilizing agents and precipitation inhibitors. The precipitation screening results showed vitamin E TPGS was an effective solubilizing agent and Pluronic F127 was a potent precipitation inhibitor for the tested compound. Interestingly, the combination of Pluronic F127 with vitamin E TPGS resulted in a synergistic effect in prolonging compound concentration upon dilution in SIF. In addition, HPMC E5 and Eudragit L100-55 were found to be effective precipitation inhibitors for the tested compounds in SGF. Furthermore, optimization DOE study results suggested a formulation sweet spot comprising HPMC, Eudragit L 100-55, vitamin E TPGS, and Pluronic F127. The lead formulation maintained the tested compound concentration at 300 µg/mL upon dilution in SIF, and more than 70% of the compound remained solubilized compared with the compound alone at <1 µg/mL of its concentration. Dosing of the solid dosage form predissolved in SGF in dogs resulted in 52% of oral bioavailability compared to 26% for the suspension control, a statistically significant increase (p = 0.002). The enhanced oral bioavailability of the tested compound could be attributed to generation and prolongation of a supersaturated drug concentration in vivo by the solubilizing agents and precipitation inhibitors. The study demonstrates that the combination approach of solubilization agents and precipitation inhibitors provides improved oral bioavailability for a poorly water-soluble weakly basic compound.


Assuntos
Química Farmacêutica/métodos , Resinas Acrílicas/química , Administração Oral , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Cães , Composição de Medicamentos/métodos , Masculino , Poloxâmero/química , Solubilidade
11.
Int J Pharm ; 393(1-2): 1-16, 2010 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-20347943

RESUMO

Drug precipitation in vivo is often an undesirable outcome after administration of a drug formulation into a human body. It may reduce drug concentration for immediate action, leading to a delayed or reduced efficacy. There are few practical in vivo assays available for evaluation of drug precipitation. Effective and efficient in vitro precipitation screening assays are highly desirable. In recent years, in vitro assays for assessment of drug precipitation potential have become available. The aim of this article is to provide the reader with a brief review of such in vitro precipitation screening assays for intravenous and oral formulations.


Assuntos
Precipitação Química , Química Farmacêutica , Ensaios de Triagem em Larga Escala , Preparações Farmacêuticas/química , Tecnologia Farmacêutica/métodos , Administração Oral , Animais , Composição de Medicamentos , Desenho de Equipamento , Ensaios de Triagem em Larga Escala/instrumentação , Humanos , Infusões Intravenosas , Injeções Intravenosas , Cinética , Miniaturização , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Farmacocinética , Solubilidade , Tecnologia Farmacêutica/instrumentação
12.
Int J Pharm ; 355(1-2): 31-7, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18299178

RESUMO

In this study, we screened surfactants and their combinations at low concentrations as potentially potent inhibitors of drug precipitation in an aqueous medium. Nine surfactants (including Pluronic F127, Pluronic F108, and Pluronic F68) were evaluated at concentrations below their critical micelle concentrations (CMCs) using an in vitro precipitation assay. A model compound used in this study showed a sharp pH-dependent solubility profile and was much more soluble in simulated gastric fluid (SGF) (pH 1.2) than in simulated intestinal fluid (SIF) (pH 7.4). The compound was first dissolved in SGF with each surfactant, and the solutions were dispensed into the wells of a 96-well microtiter plate by a TECAN robot and diluted 10-fold with SIF. After a preset incubation time at room temperature, the solutions were filtrated through a 96-well filter plate, and the compound concentration in the filtrate was measured using an HPLC method. At concentrations below their CMCs, Pluronic F127 and Pluronic F108, but not Pluronic F68, inhibited the compound precipitation in SIF. Combinations of Pluronic F127 or Pluronic F108 with Vitamin E TPGS showed significantly stronger inhibition than the individual surfactants, indicating synergistic effects on inhibition of drug precipitation.


Assuntos
Poloxâmero/química , Tensoativos/química , Vitamina E/análogos & derivados , Líquidos Corporais/química , Varredura Diferencial de Calorimetria , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Excipientes , Concentração de Íons de Hidrogênio , Indicadores e Reagentes , Polietilenoglicóis/química , Vitamina E/química , Difração de Raios X
13.
Adv Drug Deliv Rev ; 60(6): 657-72, 2008 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-18222563

RESUMO

Development of solubility-enhancing formulations for poorly water-soluble compounds always poses a challenge. Conventional formulation screening assays are potentially time-consuming and labor-intensive and, moreover, require a large amount of a compound; they are not ideal when compound availability and testing time are limited. In recent years, in-vitro screening assays that are rapid, inexpensive, minimally labor-intensive, and require only small quantities of a compound have become available. These advanced assays allow high-throughput automation, miniaturization, and parallel processing, thereby enabling scientists to rapidly identify solubility-enhancing formulations with milligram or sub-milligram quantities of an active pharmaceutical ingredient (API). This article reviews these assays for rapidly screening the aqueous solubility of lead compounds and the solubility-enhancing formulations with limited quantities of API.


Assuntos
Química Farmacêutica/métodos , Miniaturização/métodos , Preparações Farmacêuticas/química , Automação/métodos , Cinética , Solubilidade , Solventes , Termodinâmica
14.
J Pharm Sci ; 96(11): 2957-69, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17705287

RESUMO

A precipitation screening method using a 96-well microtiter plate was developed to evaluate in vitro drug precipitation kinetics of liquid formulations for poorly water-soluble compounds, using milligram quantities of compounds and milliliter volumes of biorelevant media. By using this method we identified three formulations showing distinct in vitro precipitation kinetics (fast, slow, and no precipitation) for a model new molecular entity (JNJ-25894934). The in vitro precipitation profiles in simulated intestinal fluid (SIF), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF) were compared with those measured by a USP dissolution method, and with in vivo absorption at the fasted and fed states in canine pharmacokinetic (PK) studies. The precipitation kinetics of all three formulations in the initial hours measured by the screening method correlated to those determined by the USP method (R(2) = 0.96). The PK results showed that the fast-precipitation formulation had the lowest bioavailability. However, a similar bioavailability was observed for the slow- and no-precipitation formulations. The oral bioavailability of JNJ-25894934 at the fed state was also significantly higher than that at the fasted state for all three formulations (p < 0.05). In addition, the in vitro precipitation profiles in FeSSIF correlated better with in vivo absorption than those in SIF and FaSSIF.


Assuntos
Preparações Farmacêuticas/química , Farmacocinética , Animais , Precipitação Química , Química Farmacêutica , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Preparações Farmacêuticas/sangue , Polietilenoglicóis/química , Solubilidade , Estearatos/química
15.
Int J Pharm ; 342(1-2): 201-7, 2007 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-17560055

RESUMO

In this study, we present a novel approach of nanosizing a drug/polymeric complex to increase both solubility and dissolution rate of poorly water-soluble compounds. A hydrophilic polymer, lambda-carrageenan, was first complexed with a model poorly water-soluble compound to increase the compound's aqueous solubility. The compound/carrageenan complex was further nanosized by wet-milling to enhance the dissolution rate. By complexing with carrageenan, the compound became amorphous in the complex. Using additional carrageenan as a stabilizer for nanosizing, a nanosuspension of a compound/carrageenan complex with a median particle size of about 0.3 microm was successfully developed. The particle size of the nanosuspension did not increase significantly during the lyophilization process and was stable for at least 39 days at room temperature after lyophilization. This approach of nanosizing a drug/carrageenan complex increased the aqueous solubility of the compound from less than 1 microg/mL to 39 microg/mL. In addition to increasing aqueous solubility, a nanosized compound/carrageenan complex had a faster dissolution rate than the complex, the free compound, and the nanosuspension of the free compound.


Assuntos
Carragenina/química , Nanopartículas , Preparações Farmacêuticas/administração & dosagem , Varredura Diferencial de Calorimetria , Fenômenos Químicos , Físico-Química , Cromatografia Líquida de Alta Pressão , Composição de Medicamentos , Estabilidade de Medicamentos , Excipientes , Liofilização , Cinética , Nanotecnologia , Tamanho da Partícula , Solubilidade , Difração de Raios X
16.
J Pharm Sci ; 96(6): 1548-63, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17094139

RESUMO

We have developed an efficient screening method to identify liquid and semisolid formulations for low-solubility compounds. The method is most suitable for identifying dosing vehicles for compounds in lead optimization, where compound supply is limited and long-term stability is not a requirement. Dilute compound and excipient stock solutions are prepared in organic solvent and then dispensed and mixed in 96-well plates. The solvent is removed in a vacuum centrifuge evaporator, leaving neat formulation (e.g., 10-40 microg compound, 0.4 mg excipient) at the bottom of each well. After an aging step, an aqueous dilution medium is added and the plates are incubated (agitation by orbital shaking). The diluted formulations are then filtered and analyzed by ultraviolet (UV) absorbance or high-performance liquid chromatography (HPLC). To illustrate the method, two compounds (aqueous solubility

Assuntos
Química Farmacêutica , Excipientes/administração & dosagem , Solubilidade , Cromatografia Líquida de Alta Pressão , Solventes , Espectrofotometria Ultravioleta
17.
Int J Pharm ; 336(1): 58-66, 2007 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-17174492

RESUMO

An insulin/lauryl sulfate complex was prepared by hydrophobic ion pairing (HIP). The physiochemical and biological properties of the HIP complex were characterized using octanol/water partition measurement, isothermal titration calorimetry (ITC), ultraviolet-circular dichroism (UV-CD) and Fourier transform infrared spectroscopy (FTIR). Sodium dodecyl sulfate (SDS) bound to the insulin in a stoichiometric manner. The formed complex exhibited lipophilicity, and its insulin retained its native structure integrity. The in vivo bioactivity of the complex insulin was evaluated in rats by monitoring the plasma glucose level after intravenous (i.v.) injection, and the glucose level was compared with that for free insulin. The pharmacodynamic study result in rats showed that the complex insulin had in vivo bioactivity comparable to free insulin.


Assuntos
Interações Hidrofóbicas e Hidrofílicas , Insulina/química , Dodecilsulfato de Sódio/química , 1-Octanol/química , Animais , Área Sob a Curva , Glicemia , Varredura Diferencial de Calorimetria , Cromatografia Líquida de Alta Pressão , Dicroísmo Circular , Feminino , Insulina/administração & dosagem , Insulina/farmacocinética , Masculino , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier
18.
Int J Pharm ; 336(1): 1-11, 2007 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-17178444

RESUMO

In this article, we present a parallel experimentation approach to rapidly identify a solubility-enhancing formulation that improved the bioavailability of a poorly water-soluble compound using milligrams of material. The lead compound and a panel of excipients were dissolved in n-propanol and dispensed into the wells of a 96-well microtiter plate by a TECAN robot. Following solvent evaporation, the neat formulations were diluted with an aqueous buffer, and incubated for 24h. The solubilization capacity of the excipients for the compound at 24h (SC(24h)), was determined by HPLC, and compared with its solubility in the corresponding neat formulations determined by a bench-scale method. The ranking order of solubilization capacity of the five tested formulations for this compound by this microscreening assay is same as the ranking order of the compound solubility in the neat formulations. Several formulations that achieved the target aqueous solubility were identified using the screening method. One of the top formulations, an aqueous solution of the compound containing 20% Tween 80 by weight, increased the compound solubility from less than 2 microg/mL to at least 10mg/mL. In a rat pharmacokinetic (PK) study, the Tween 80 formulation achieved 26.6% of bioavailability, a significant improvement over 3.4% of bioavailability for the aqueous Methocel formulation (p<0.01). The results in the study suggest that this parallel screening assay can be potentially used to rapidly identify solubility-enhancing formulations for an improved bioavailability of poorly water-soluble compounds using milligram quantities of material.


Assuntos
Química Farmacêutica/métodos , Indanos/farmacocinética , Pirazóis/farmacocinética , Tensoativos/química , Animais , Área Sob a Curva , Disponibilidade Biológica , Excipientes/química , Feminino , Concentração de Íons de Hidrogênio , Indanos/administração & dosagem , Indanos/química , Masculino , Peso Molecular , Permeabilidade , Soluções Farmacêuticas/química , Pirazóis/administração & dosagem , Pirazóis/química , Ratos , Ratos Sprague-Dawley , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Solubilidade , Temperatura de Transição , Água/química
19.
Pharm Res ; 22(4): 518-22, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15846458

RESUMO

PURPOSE: This study evaluated the effect of the imaginary component of the refractive index on laser diffraction particle size data for pharmaceutical samples. METHODS: Excipient particles 1-5 microm in diameter (irregular morphology) were measured by laser diffraction. Optical parameters were obtained and verified based on comparison of calculated vs. actual particle volume fraction. RESULTS: Inappropriate imaginary components of the refractive index can lead to inaccurate results, including false peaks in the size distribution. For laser diffraction measurements, obtaining appropriate or "effective" imaginary components of the refractive index was not always straightforward. When the recommended criteria such as the concentration match and the fit of the scattering data gave similar results for very different calculated size distributions, a supplemental technique, microscopy with image analysis, was used to decide between the alternatives. Use of effective optical parameters produced a good match between laser diffraction data and microscopy/image analysis data. CONCLUSIONS: The imaginary component of the refractive index can have a major impact on particle size results calculated from laser diffraction data. When performed properly, laser diffraction and microscopy with image analysis can yield comparable results.


Assuntos
Excipientes/química , Lasers , Refratometria , Tecnologia Farmacêutica , Aumento da Imagem , Luz , Microscopia/métodos , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Espalhamento de Radiação , Soroalbumina Bovina/química , Cloreto de Sódio/química , Suspensões
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