Electrospray encapsulation of hydrophilic and hydrophobic drugs in poly(L-lactic acid) nanoparticles.

An electrospray method is developed for preparation of beclomethasone-dipropionate- and salbutamol-sulfate-loaded biodegradable poly(L-lactic acid) nanoparticles. Different set-up parameters for electrospraying are examined on particle size, and preparation conditions are optimized for producing spherical-drug-loaded nanoscale particles by controllable processing parameters. Polylactide (PLA)-drug nanoparticles with average diameters of around 200 nm are achieved in a stable cone-jet mode with a flow rate of 4 microL min(-1), polymer concentration of 1%, and ammonium hydroxide content of 0.05%. Morphology and size of the drug-polymer nanoparticles are analyzed by scanning electron microscopy and transmission electron microscopy. Changes in the crystallinity of the PLA polymer and the model drugs are detected by X-ray powder diffraction, and the absence of molecular interactions are confirmed by thermal analyses. The results indicate clearly that electrospraying is a potential method for producing polymeric nanoparticles and for encapsulating both hydrophilic and hydrophobic drugs efficiently into the nanoparticles.

Understanding processing-induced phase transformations in erythromycin-PEG 6000 solid dispersions.

Since the quality and performance of a pharmaceutical solid formulation depend on solid state of the drug and excipients, a thorough investigation of potential processing-induced transformations (PITs) of the ingredients is required. In this study, the physical phenomena taking place during formulation of erythromycin (EM) dihydrate solid dispersions with polyethylene glycol (PEG) 6000 by melting were investigated. PITs were monitored in situ using variable temperature X-ray powder diffraction (VT-XRPD), differential scanning calorimetry (DSC), and hot-stage microscopy (HSM). Possible intermolecular interactions between the drug and polymer in the solid state were further studied by Fourier transform infrared (FTIR) spectroscopy. While in the absence of PEG the dehydration was the only transformation observed, hot-melt processing with the polymer caused the drug to undergo multiple phase transformations (EM dihydrate --> EM dehydrate --> EM anhydrate). This alteration in phase behavior of EM was attributed to the ability of PEG in promoting nucleation and crystal growth of the EM anhydrate through a solvent-mediated route. In situ monitoring of solid dispersion formation, especially by VT-XRPD and HSM, enabled both early-stage detection of phase transformations during the hot-melt processing and better process understanding.

Role of water in the physical stability of solid dosage formulations.

The interaction of moisture with pharmaceutical solids is highly crucial to an understanding of water-based processes, for example, manufacturing processes or prediction of solid dosage form stability and shelf life. Both the active pharmaceutical ingredient (API) and excipients in the formulation have different moisture sorption properties that can result in unexpected processing-induced phase transitions and they can affect solid-state phase transitions in the final dosage forms. The character of excipient effects on the stability of formulation. Phase transformations in formulations can lead to instability in physicochemical, biopharmaceutical, and processing properties of products. The aim of the present study was to investigate the water sorption properties of different excipients, model the sorption isotherms, examine the phase transitions, and identify differences of excipients in solid dosage form stability using dynamic vapor sorption analysis, near-infrared spectroscopy, and X-ray diffraction methods. The thermal processing was carried out with a variable temperature X-ray powder diffractometer to compare the dehydration behavior of wet excipients and evaluate solid-state properties during heating. These results showed that despite some limitations, moisture sorption isotherms of excipients are useful in predicting solid-state stability, interactions at early stages of formulation development, and effects of moisture on physicochemical properties of the final dosage forms.

Physical stability and moisture sorption of aqueous chitosan-amylose starch films plasticized with polyols.

The short-term stability and the water sorption of films prepared from binary mixtures of chitosan and native amylose maize starch (Hylon VII) were evaluated using free films. The aqueous polymer solutions of the free films contained 2% (w/w) film formers, glycerol, or erythritol as a plasticizer, as well as acetic acid (1%) and purified water. Characterization of the present fresh and conditioned film formers and free films was done using X-ray diffraction analysis, determination of moisture sorption isotherms, and near infrared spectroscopy. The results indicated that clear changes in the crystallinity of the films are evident within a 3-month period of storage, and the changes in the solid state are dependent on the plasticizer and storage conditions. When stored at ambient conditions for 3 months, the aqueous chitosan-amylose starch films plasticized with erythritol exhibited a partly crystalline structure. This was as a result of sugar recrystallisation due to the high hydrogen bonding. The respective films plasticized with glycerol and stored at 25 degrees C/60% relative humidity (RH) or at 40 degrees C/75% RH remained flexible and amorphous for at least 3 months. The water sorption of the free films greatly increased as a function of storage time at 75 and 95% RH. The second derivative spectra of starting material and free films were capable of distinguishing the internal water from the free water after storage at different relative humidities. Free water resulted in a separate band at a lower wavelength (1903 nm) in comparison to the structured absorbed water band at 1920 nm, in the case of films the free water resulted in a band around 1900 nm.

Role of excipients in hydrate formation kinetics of theophylline in wet masses studied by near-infrared spectroscopy.

Hydrate formation is a phase transition, which can occur during wet granulation. This kind of processing-induced transformation (PIT) can influence the quality of a finished product. The aim of the study was to investigate the effect of excipients on the kinetics of hydrate formation in wet masses. Anhydrous theophylline was chosen as the hydrate-forming model drug compound and two excipients, silicified microcrystalline cellulose (SMCC) and alpha-lactose monohydrate, with different water absorbing properties, were used in formulation. An early stage of wet massing was studied with anhydrous theophylline and its 1:1 (w/w) mixtures with alpha-lactose monohydrate and SMCC with 0.1g/g of purified water. The changes in the state of water were monitored using near-infrared spectroscopy, and the conversion of the crystal structure was verified using X-ray powder diffraction (XRPD). SMCC decreased the hydrate formation rate by absorbing water, but did not inhibit it. The results suggest that alpha-lactose monohydrate slightly increased the hydrate formation rate in comparison with a mass comprising only anhydrous theophylline.

Improved entrapment efficiency of hydrophilic drug substance during nanoprecipitation of poly(l)lactide nanoparticles.

The purpose of this research was to improve the entrapment efficiency of a model hydrophilic drug substance, sodium cromoglycate, loaded inside polylactic acid nanoparticles by a modified nanoprecipitation method. The effect of formulation parameters was studied to improve the entrapment efficiency of the drug substance inside the nanoparticles. Several parameters (changes in the amount of model drug, solvent selection, electrolyte addition, pH alteration) were tested in order to increase the loading of the hydrophilic drug in the hydrophobic nanoparticles. Lowering of the pH was the most efficient way to increase the drug loading; up to approximately 70% of the sodium cromoglycate used in the particle formation process could be loaded inside the particles. The loading efficiency without the pH change was around 10% to 15% at maximum. The crystallinity values and crystal habits of the sodium cromoglycate nanoparticles were studied (x-ray diffraction) before and after the lowering of the pH. The change in pH conditions during the nanoprecipitation process did not affect markedly the crystallinity properties of the drug substance. According to this study, it is possible to improve the entrapment efficiency of hydrophilic sodium cromoglycate inside of the nanoparticles by small changes in the process parameters without alterations in the physical properties of the original drug substance.

The effect of cosolvents on the formulation of nanoparticles from low-molecular-weight poly(l)lactide.

The aim of this study was to formulate nanoparticles from poly(l)lactide by a modified nanoprecipitation method. The main focus was to study the effect of cosolvent selection on the shape, size, formation efficiency, degree of crystallinity, x-ray diffraction (XRD) reflection pattern, and zeta potential value of the particles. Low-molecular-weight (2000 g/mol) poly(l)lactide was used as a polymer, and sodium cromoglycate was used as a drug. Acetone, ethanol, and methanol were selected as cosolvents. Optimal nanoparticles were achieved with ethanol as a cosolvent, and the formation efficiency of the particles was also higher with ethanol as compared with acetone or methanol. The particles formulated by ethanol and acetone appeared round and smooth, while with methanol they were slightly angular. When the volume of the inner phase was decreased during the nanoprecipitation process, the mean particle size was also decreased with all the solvents, but the particles were more prone to aggregate. The XRD reflection pattern and the degree of crystallinity were more dependent on the amount of the solvents in the inner phase than on the properties of the individual cosolvents. The zeta potential values of all the particle batches were slightly negative, which partially explains the increased tendency toward particle aggregation.