RESUMEN
In a former publication the authors showed that low amounts of amorphous content (LOQ of 0.5%) in a hydrophobic model API (Ciclesonide) can be measured with an individually adjusted one-step dynamic organic vapor sorption (DVS). In this investigation the applicability is tested on various APIs which differ in lipophilicity (poor water solubility) and hygroscopicity (absorption of water). The vapor sorption method proved to be applicable in almost all cases. Moisture sorption isotherms were determined for all five investigated crystalline and amorphous APIs. However, it was necessary to select the parameters individually for each API. The used solvents (water, methanol, isopropanol and methylene chloride) and the humidity-levels (0.05 p/p0 until 0.5 p/p0) were chosen carefully because otherwise the amorphous amounts switch to their crystalline counterparts and are not detectable. The production of fully amorphous samples (absence of crystalline material measured by DSC, mDSC and XRPD) was optimized over several trials. As successfully methods proved ball-milling, freeze-drying, spray-drying and/or quench cooling. In the next step these fully amorphous amounts were blended with crystalline starting material to calibration curves (Turbula blender, influence of electrostatic charge to homogeneity) for the calculation of amorphous content. In summary, the following presented methods were used to determine and quantify low amorphous amounts (between 1.5% and 17.0%) in jet-milled powders (grinding pressure of 8bar, 1-3 grinding cycles), respectively.
Asunto(s)
Preparaciones Farmacéuticas/química , Tecnología Farmacéutica/métodos , Absorción Fisicoquímica , Química Farmacéutica , Cristalización , Interacciones Hidrofóbicas e Hidrofílicas , Tamaño de la Partícula , Preparaciones Farmacéuticas/normas , Tecnología Farmacéutica/normas , Volatilización , Agua/químicaRESUMEN
The effects of different manufacturing methods to induce formation of amorphous content, changes of physico-chemical characteristics of powder blends and changes of aerodynamic properties over storage time (6months) analyzed with the Next Generation Impactor (NGI) are investigated. Earlier studies have shown that standard pharmaceutical operations lead to structural disorders which may influence drug delivery and product stability. In this investigation, fully amorphous drug samples produced by spray-drying (SD) and ball-milling (BM) as well as semi-crystalline samples (produced by blending and micronization) are studied and compared to fully crystalline starting material. The amorphous content of these hydrophilic and hydrophobic active pharmaceutical ingredients (APIs) was determined using a validated one-step DVS-method. For the conducted blending and micronization tests, amorphous amounts up to a maximum of 5.1% for salbutamol sulfate (SBS) and 17.0% for ciclesonide (CS) were measured. In order to investigate the impact of small amorphous amounts, inhalable homogenous powder mixtures with very high and low amorphous content and a defined particle size were prepared with a Turbula blender for each API. These blends were stored (6months, 45% RH, room temperature) to evaluate the influence of amorphous amounts on storage stability. The fine particle fraction (FPF: % of emitted dose<5µm) was determined with the NGI at defined time points. The amorphous amounts showed a major effect on dispersion behavior, the mixtures of the two APIs showed differences at the beginning of the study and significant differences in storage stability. The FPF values for SBS decreased during storage (FPF: from 35% to <27%) for the blend with high amorphous amounts, in contrast the initially re-crystallized sample achieved a comparable constant level of about 25%. For the hydrophobic CS a constantly increasing FPF (from 6% to >15%) over storage time for both types of blends was determined. Therefore, prolonged stability of amorphous parts and an incalculable behavior for CS blends are supposed, in contrast, SBS showed a controllable FPF after conditioning.
Asunto(s)
Albuterol/química , Química Farmacéutica/métodos , Sistemas de Liberación de Medicamentos , Pregnenodionas/química , Administración por Inhalación , Albuterol/administración & dosificación , Cristalización , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Inhaladores de Polvo Seco , Interacciones Hidrofóbicas e Hidrofílicas , Tamaño de la Partícula , Polvos , Pregnenodionas/administración & dosificación , Tecnología Farmacéutica/métodos , Factores de TiempoRESUMEN
Today, a variety of devices for dry powder inhalers (DPIs) is available and many different formulations for optimized deposition in the lung are developed. However, during the production of powder inhalers, processing steps may induce changes to both, the carrier and active pharmaceutical ingredients (APIs). It is well known that standard pharmaceutical operations may lead to structural changes, crystal defects and amorphous regions. Especially operations such as milling, blending and even sieving generate these effects. These disorders may induce re-crystallization and particle size changes post-production which have a huge influence on drug delivery and product stability. In this study, pilot tests with a polar solvent (water) and hydrophilic drug (Salbutamol sulfate) were performed to receive a first impression on further possible implementation of hydrophobic samples with organic solvents. Thereafter, a reliable method for the accurate detection of low amounts of amorphous content is described up to a limit of quantification (LOQ) of 0.5% for a hydrophobic model API (Ciclesonide). The organic vapor sorption method which is a gravimetric method quantifies exactly these low amounts of amorphous content in the hydrophobic powder once the suitable solvent (isopropanol), the correct p/p0 value (0.1) and the exact temperature (25°C) have been found. Afterward it was possible to quantitate low amorphous amounts in jet-milled powders (0.5-17.0%). In summary, the data of the study led to a clearer understanding in what quantity amorphous parts were generated in single production steps and how variable these parts behave to fully crystalline material. Nevertheless it showed how difficult it was to re-crystallize hydrophobic material with water vapor over a short period. For the individual samples it was possible to determine the single humidity at which the material starts to re-crystallize, the behavior against different nonpolar solvents and the calculation of the reduction of the glass transition temperature (Tg) according to the Gordon-Taylor equation.
Asunto(s)
2-Propanol/química , Albuterol/administración & dosificación , Pregnenodionas/administración & dosificación , Agua/química , Albuterol/química , Química Farmacéutica/métodos , Cristalización , Sistemas de Liberación de Medicamentos , Inhaladores de Polvo Seco , Humedad , Interacciones Hidrofóbicas e Hidrofílicas , Tamaño de la Partícula , Proyectos Piloto , Polvos , Pregnenodionas/química , Solventes/química , Temperatura de TransiciónRESUMEN
PURPOSE: The aim of this study was to investigate influencing factors on the dissolution test for powders for pulmonary delivery with USP apparatus 2 (paddle apparatus). METHODS: We investigated the influence of dose collection method, membrane holder type and the presence of surfactants on the dissolution process. Furthermore, we modeled the in vitro dissolution process to identify influencing factors on the dissolution process of inhaled formulations based on the Nernst-Brunner equation. RESULTS: A homogenous distribution of the powder was required to eliminate mass dependent dissolution profiles. This was also found by modeling the dissolution process under ideal conditions. Additionally, it could be shown that influence on the diffusion pathway depends on the solubility of the substance. CONCLUSION: We demonstrated that the use of 0.02% DPPC in the dissolution media results in the most discriminating and reproducible dissolution profiles. In the model section we demonstrated that the dissolution process depends strongly on saturation solubility and particle size. Under defined assumptions we were able show that the model is predicting the experimental dissolution profiles.
Asunto(s)
Preparaciones Farmacéuticas/química , Polvos/química , Administración por Inhalación , Química Farmacéutica/métodos , Pulmón/efectos de los fármacos , Modelos Químicos , Tamaño de la Partícula , Preparaciones Farmacéuticas/administración & dosificación , Polvos/administración & dosificación , Solubilidad , Tecnología Farmacéutica/métodosRESUMEN
In the last decades, dry powder inhalation has become a very attractive option for pulmonary drug delivery to treat lung diseases like cystic fibroses and lung infections. In contrast to the traditional pulmonary application of drugs for asthma and chronic obstructive pulmonary disease, these therapies require higher lung doses to be administered. The developments and improvements toward high dose powder pulmonary drug delivery are summarized and discussed in this chapter. These include the invention and improvement of novel inhaler devices as well as the further development of formulation principles and new powder engineering methods. The implementation of these strategies is subsequently described for some prototypes and formulations in research and development stage as well as for already marketed dry powder products. Finally, possible adverse effects that can occur after inhalation of high powder doses are shortly addressed.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Pulmón/metabolismo , Preparaciones Farmacéuticas/administración & dosificación , Administración por Inhalación , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/metabolismo , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de Medicamentos/efectos adversos , Sistemas de Liberación de Medicamentos/instrumentación , Inhaladores de Polvo Seco , Humanos , Pulmón/efectos de los fármacos , Inhaladores de Dosis Medida , Preparaciones Farmacéuticas/química , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones del Sistema Respiratorio/metabolismoRESUMEN
PURPOSE: A new dry powder inhalation technology creates inhalable particles from a coherent lyophilized bulk at the time of inhalation. The aim of this study was to evaluate several approaches to improve the fine particle fraction (FPF) and to understand underlying mechanisms. METHODS: Lysozyme was chosen as model drug. Phenylalanine and valine were added, and the freezing process was varied. Lyophilisate characteristics as well as aerosolization behavior was analyzed. RESULTS: The addition of the crystalline amino acids rendered a dose independent three-fold increase of the FPF. This is possibly due to enhanced fracture properties of the lyophilisates upon impact of the air stream and reduced particle agglomeration/cohesion caused by a rougher surface. This positive effect was well preserved over 3 months of storage. The structure of the lyophilisate was influenced by the freezing process which in turn affected the aerosolization behavior. Liquid nitrogen and vacuum-induced freezing performed best, doubling the FPF. The special cake morphology with elongated channels enabled easy disintegration. The resulting large porous particles comprise a low density being advantageous for a high FPF. CONCLUSION: The variation of the lyophilization process and formulation utilizing excipients enabled an optimization of the FPF of the novel lyophilisate based DPI system.
Asunto(s)
Química Farmacéutica/métodos , Inhaladores de Polvo Seco/métodos , Muramidasa/química , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Excipientes/síntesis química , Liofilización/métodos , Tamaño de la Partícula , Fenilalanina/química , Valina/químicaRESUMEN
Dry powder inhalers and dry powder formulations experience a growing interest and are the subject of continuous further development. In this study the objective was to evaluate the possible aerosolization of lyophilisates by an air impact and to prove this new concept of creating individual inhalable particles from a coherent bulk at the time of inhalation. Therefore an output test system for disintegration of the lyophilisate and for delivery of the generated fine particles was developed. The output system uses compressed air at a preselectable pressure for reproducible generation of inhalable particles. In order to understand the aerosolization of lyophilisates by the air impact, different single excipient formulations of amino acids and sugars were investigated. Besides the characterization of the different formulations by microscopy and X-ray diffractometry, we focused mainly on the particle size distributions (PSD) of the dispersed particles. Thereby the geometric PSD was analyzed by laser diffraction, whereas the aerodynamic PSD was characterized by time of flight and Andersen cascade impactor analysis. The destruction of the porous structure of the lyophilisates resulted in large geometric particle sizes but aerodynamic particle sizes in the inhalable range with relatively large fine particle fractions (FPF) between 20% and 50% calculated as a percentage of the metered dose. Despite potential differences in freezing behavior and thus cake structure within lyophilization batches, we attained reproducible fine particle fractions. Overall, it is concluded that the controlled disintegration of lyophilisates into inhalable particles by an air impact is possible and substantial FPF are achieved. Therefore, the method represents a promising new dry powder inhalation technology.
Asunto(s)
Inhaladores de Polvo Seco/instrumentación , Excipientes/química , Polvos/química , Administración por Inhalación , Aerosoles/química , Química Farmacéutica , Aire Comprimido , Sistemas de Liberación de Medicamentos , Inhaladores de Polvo Seco/métodos , Diseño de Equipo , Excipientes/administración & dosificación , Liofilización/métodos , Modelos Teóricos , Tamaño de la Partícula , Fenilalanina/administración & dosificación , Fenilalanina/química , Polvos/administración & dosificación , Valina/administración & dosificación , Valina/químicaRESUMEN
This study aims towards a deeper understanding of the correlation between particle morphology, cohesion forces, and aerosol performance of spray dried powders for inhalation. Therefore, forces affecting cohesion and dispersion are considered and some novel contact models are introduced to explain the improved powder dispersibility of corrugated particles. Particles with different degrees of corrugation are prepared by spray drying and characterized. Powder dispersibility is measured by positioning a dry powder inhaler in front of the laser diffraction device. The particle sizes of all powders are in the range of x(50) = 2.11 +/- 0.15 microm. The ratio of mass specific surface area S(m) to volume specific surface area S(V) rises from 0.54 cm(3)/g (spherical particles) to 0.83 cm(3)/g (most corrugation). The fine particle fraction (FPF) rises significantly with increasing corrugation at 24 L/min which can be explained by a distinct difference in powder dispersibility. From theoretical models a reduction in cohesion up to 90% can be estimated for corrugated particles compared to spherical particles. Advantages in powder dispersibility can be expected for particles having a lower density and smaller radius of curvature in the contact zone. Both characteristics are given in case of corrugated particles and can be optimized to a certain degree of corrugation.