The effect of spray drying solutions of polyethylene glycol (PEG) and lactose/PEG on their physicochemical properties

The effect of spray drying polyethylene glycol (PEG) 4000 and lactose/PEG solutions was investigated. Micro-spherical PEG particles were successfully prepared from ethanol, which allowed lower outlet temperatures than water. The product was crystalline and consisted of rough spheres or rod like particles. In the case of lactose/PEG composites, spray dried from water, the crystallinity of both components was reduced on spray drying, the extent being dependent on the starting composition. Spray dried lactose/PEG with PEG present as 10% by weight was found to be the most amorphous of the systems prepared. Conversion to more crystalline products occurred over time, the rates of conversion being dependent on temperature and humidity. On storage at low humidity (31-34%) amorphous lactose in lactose/PEG spray dried systems converts to anhydrous crystalline lactose while at high humidity (75% RH) the monohydrate is formed. The rate of transformation of amorphous lactose to the crystalline monohydrate form, at high relative humidity, was quantified using the Avrami equation applied both to X-ray diffraction (XRD) peak intensity and heat of fusion data. Crystallisation of lactose appeared to be retarded at low PEG concentrations, where PEG was present predominantly in a non-crystalline state, but was accelerated at higher PEG contents.     

Aerosolisation of beclomethasone dipropionate using spray dried lactose/polyethylene glycol carriers.

The aim of this study was to characterize the physical properties of spray dried lactose in the presence of different polyethylene glycols (PEG 400, PEG 3000 and PEG 6000) and to evaluate their performance as carriers for dry powder inhaler (DPI) formulations. The efficiency of spray dried lactose/PEG carriers in aerosolisation of beclomethasone dipropionate (BD), a model hydrophobic drug, was compared to Pharmatose 325 M (L325), spray dried lactose alone (SDL), and also a sieved (< 38 microm) fraction of alpha-lactose monohydrate (SL). In vitro deposition analysis was performed using a twin stage liquid impinger at a flow rate of 60 l/min through a Spinhaler. The deposition profiles of the drug from binary formulations composed of BD and spray dried lactose/PEG carriers were also compared to ternary formulations containing large and fine lactose carriers. Differential scanning calorimetry and X-ray diffraction data showed the presence of alpha-anhydrous lactose in spray dried lactose/PEG crystalline powders. Spray drying of lactose in the presence of PEG 400 resulted in the production of a powder (SDL-PEG400) with lower alpha-lactose monohydrate content, and also smaller particle size distribution than those obtained in the presence of PEG 3000 (SDL-PEG3000) or PEG 6000 (SDL-PEG6000). All formulations showed different deposition profiles, except those containing SDL-PEG3000 or SDL-PEG6000 which exhibited similar data. The fine particle fraction of aerosolised BD varied from 6.26 +/- 1.07 (for L325) to 25.87 +/- 5.33 (for SDL-PEG3000). All deposition profiles of BD aerosolised from SDL-PEG3000 were significantly higher (P < 0.01) than those produced by binary and ternary formulations containing L325, a coarse lactose commercially available for DPI formulations. The differences observed in deposition data for various carriers were interpreted according to their physical properties. It was concluded that particle size distribution, morphology and specific surface texture of SDL-PEG3000 and SDL-PEG6000 were important factors influencing their efficiency as small carriers for DPI formulations.     

Predicting the physical state of spray dried composites: salbutamol sulphate/lactose and salbutamol sulphate/polyethylene glycol co-spray dried systems

The effect of spray drying salbutamol sulphate, salbutamol sulphate/lactose and salbutamol sulphate/polyethylene glycol (PEG) solutions was investigated. Co-spray drying salbutamol sulphate with lactose, which is amorphous when spray dried alone, resulted in amorphous composites. Co-spray drying salbutamol sulphate with PEG 4000 and PEG 20,000, which do not form amorphous systems when spray dried alone, resulted in systems of varying crystallinity, the crystallinity depending on the weight ratio of polymer to drug. Examination of the physical properties of these salbutamol sulphate co-spray dried systems and those of bendroflumethiazide/PEG and lactose/PEG composites suggested that the formation and physical stability of amorphous composites prepared by spray drying is dependent on whether the glass transition temperature, Tg, of one of the two components is high enough to result in a Tg of the composite sufficiently high that the Kauzmann temperature of the mix is greater than the temperature of storage. The modified Gordon-Taylor equation proved to be useful in predicting the likelihood that a two-component composite will be amorphous on spray drying. Furthermore, the Gordon-Taylor equation was also useful in predicting the likely physical stability of amorphous two component composites and predicted that even polymers with apparently low Tgs, such as PEGs, may be stabilised in an amorphous composite by a suitable additive having a sufficiently high Tg.     

The effect of co-spray drying with polyethylene glycol 4000 on the crystallinity and physical form of lactose

The effect of spray drying lactose alone and in the presence of polyethylene glycol 4000 was investigated. Lactose was added to distilled water to give concentrations of 10, 20, 30 and 40g/100ml at room temperature and each spray dried in turn. Identical samples were prepared to which polyethylene glycol (PEG) 4000 was added (12% by weight of lactose) prior to spray drying. Microcalorimetric and X-ray diffraction studies showed that spray drying lactose solutions produced completely amorphous material due to rapid solidification during the spray drying process, whereas lactose suspensions yielded partially crystalline products due to crystalline material that remained in suspension. However, all the PEG/lactose (12%w/w) co-spray dried products were found to be crystalline. It can be inferred that the solidification rates of the lactose in the presence of PEG must have been slower than that of lactose alone which allowed PEG and lactose to crystallize. The PEG/lactose products that were spray dried from solution consisted of alpha-anhydrous, alpha-monohydrate, beta-lactose and PEG extended chain polymorph, whereas those formed from suspension PEG/lactose samples consisted of only alpha-anhydrous, alpha-monohydrate and extended chain PEG crystals. PEG probably caused the more concentrated lactose suspensions to crystallize slowly due to the strong hydrogen bonding between PEG and water, which allowed growth on the alpha-lactose seed crystals.     

Investigation of the adjuvant effect of polyethylene glycol (PEG) 400 in BALB/c mice.

In the formulation of peptide- and protein-based drugs, it is important that the pharmaceutical excipients used do not potentiate possible immunogenic properties of the drug substance. Polyethylene glycols (PEGs) are widely used excipients e.g. in parenteralia and in formulations for nasal application. The immunomodulating properties of PEG 400 were investigated in this study using hen egg ovalbumin (OA) as the model immunogen. OA was dissolved in saline, 10% PEG 400 in saline or undiluted PEG 400 and injected subcutaneously into the neck region of BALB/cJ mice. The levels of OA-specific IgE, IgG1 and IgG2a antibodies were measured. The 10% solution of PEG 400 did not have any immunomodulating properties, whereas the undiluted product gave rise to immunosuppression when compared with the saline control. Neither 10% nor the 100% PEG 400 preparation possessed adjuvant activity under the conditions of the study.     

The influence of additives on the recrystallisation of amorphous spray dried lactose

Amorphous material in crystals can constitute reactive ‘hot spots’, which can be centres for chemical degradation or physical transitions, leading to product instability. Problems have been encountered in studying small amounts of amorphous content for powdered systems, due to poor sensitivity of the majority of techniques. Isothermal microcalorimetry has been shown to have good resolution for cases where the amorphous content of the powder can be made to recrystallise in the instrument. In this study amorphous lactose has been investigated, being recrystallised by exposure to air at 75% RH. The lactose has been studied in two layers separated by varying amounts of glass beads (inert carrier), magnesium stearate (hydrophobic excipient), or microcrystalline cellulose (hygroscopic excipient). Significant differences were observed in the time needed to cause recrystallisation when amorphous material was separated by these different additives. Glass beads had only a small effect, but magnesium stearate caused an increased lag time prior to the recrystallisation event. In both these cases the lactose all recrystallised at one time, even though it was divided into two physically separated regions. A layer of microcrystalline cellulose between two layers of amorphous lactose resulted in a long lag time prior to recrystallisation, as it removed considerable amounts of water vapour from the atmosphere, thus preventing saturation of the lactose. By varying the weight of amorphous lactose in the upper and lower layers, and comparing data with the results obtained for homogeneous mixtures, it was possible to postulate a mechanism for the cooperative recrystallisation process. In essence, the water vapour is absorbed into the upper layers of the sample, and then transferred away yielding a concentration gradient through the entire sample in the cell. As the water content gradually increases in the lower layers, the rate of water absorption can become more rapid than the rate at which water is transferred away from the surface. After this time the surface saturates, starts to recrystallise thus liberating a great excess of water vapour, which is sufficient to cause the lower layers of powder to become saturated and also to recrystallise.     

The effect of spray drying solutions of bendroflumethiazide/polyethylene glycol on the physicochemical properties of the resultant materials

The physicochemical properties of co-spray dried bendroflumethiazide (BFMT)/polyethylene glycol (PEG) 4000 composites were investigated. The co-spray dried composites produced from all BFMT/polymer solutions were amorphous. BFMT/PEG 4000 10 and 20% systems consisted of smooth spherical particles approximately 0.5-4mm in diameter. Spray drying resulted in no significant production of the main BFMT degradant, 5-trifluoromethyl-2,4-disulphamoylaniline (TFSA), and for composites consisting of 90% PEG 4000 by weight of total solids, spray drying appeared a superior method of production than the melt method which resulted in significant BFMT degradation. All BFMT/PEG compressed discs showed initial increased release of BFMT compared to discs of micronised BFMT alone, with the spray dried BFMT/PEG 4000 10% system showing initial rates two to three times that of BFMT alone. The physical stability of amorphous BFMT was reduced on inclusion of PEG 4000, recrystallisation occurring more quickly with increasing amount of PEG 4000 in the composites. PEG in the co-spray dried systems appeared to degrade on storage and recrystallised samples failed to show the presence of PEG by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) or GPC. DSC results were consistent with BFMT/PEG forming a eutectic combination rather than a monotectic system.     

Oral toxicity of polyethylene glycol (PEG 200) in monkeys and rats

Polyethylene glycols, particularly those with low molecular weights, are considered to be relatively non-toxic. Polyethylene glycol (PEG 200) was administered orally to Cynomolgus monkeys (Macaca fascicularis) and rats (Sprague-Dawley origin) for a 13-week period at dosage levels of 2 to 4 ml/kg (monkeys) and 2.5 to 5.0 ml/kg/day (rats). Pathological lesions were encountered only in monkeys and these consisted of intratubular deposition of small numbers of oxalate crystals in the renal cortex. These lesions were not associated with other clinical or pathological findings.     

Two-week aerosol inhalation study on polyethylene glycol (PEG) 3350 in F-344 rats

PEGs in the 3000 to 4000 MW range are used in many pharmaceutical and cosmetic applications; they produce little ocular or dermal irritation and have extremely low acute and subchronic toxicity by oral and dermal routes of administration. However, little information exists on the potential of aerosols of these materials to produce adverse health effects. F-344 rats were exposed to aerosols of PEG 3350 (20% w:w in water) at 0, 109, 567, or 1008 (highest attainable) mg/m3 for 6 hr/d, 5 d/wk for 2 wk. No exposure-related toxicity was found with regard to clinical signs, ophthalmology, serum chemistry, urinalysis, or gross pathology. Exposure-related effects included: a 50% increase in the neutrophil count (males only) at 1008 mg/m3; decreased body weight gain (16%) for both the 567 and 1008 mg/m3 groups (males only); absolute lung weights of both sexes were increased 10 and 18% for the 567 and 1008 mg/m3 groups, respectively. A slight increase in the number of macrophages in the alveoli was the only change observed histologically in all PEG 3350-exposed groups. Therefore, inhalation of aerosols of PEG 3350 at concentrations up to 1008 mg/m3 produced relatively little toxicity in rats, the lung was the target organ, and the no-observable-effect-level was between 109 to 567 mg/m3.     

Studies on the spray dried lactose as carrier for dry powder inhalation

The purpose of this study was to investigate the spray dried lactose as carrier for dry powder inhalation (DPI). The lactose particles were prepared by spray drying, then the particle size, shape and crystal form were characterized by laser diffraction, scanning electron microscopy (SEM), X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The spray dried lactose particles were spherical and amorphous, but would transfer to crystal form when storage humidity was above 32%. Thus, the humidity of the storage environment should be controlled below 30% strictly in order to maintain the amorphous nature of spray dried lactose which is a great benefit to DPI development.     

Application of polyethylene glycol (PEG) to the control of permeability of poly(meth)acrylate coatings

Pellets with pholedrine sulphate are coated by means of a fluid-bed process with poly(meth)acrylate materials (Eudragit RS, Eudragit E 30 D, Scopacryl D 340) and varying portions of PEG 6000. In addition to influencing drug release by change of the thickness it was studied the admixture of PEG to the films. Figure logarithm permeability coefficient vs. the portion of PEG can be used to select a coating composition with wished permeability. By application of aqueous latex dispersions (Eudragit E 30 D, Scopacryl D 340) PEG dissolves completely very fast from the coatings. On the other hand if organic lac solution (Eudragit RS) is used a stagnation of the dissolution process after some min is observed. By leaching out the PEG the structure of the resulting films is loosened and therefore its permeability is increased.     

The effect of glycerol, propylene glycol and polyethylene glycol 400 on the partition coefficient of benzophenone-3 (oxybenzone)

Sunscreen products are widely used to protect the skin from sun-related deleterious effects. The objective of the study was to investigate the potential effect of glycerol, propylene glycol and polyethylene glycol 400 on dermal absorption of oxybenzone by studying their effects on its partition coefficient. The partition coefficient was evaluated in a chloroform-water system at room temperature. It was found that glycerol and propylene glycol decreased the partition coefficient of oxybenzone, while an increase in partition coefficient was observed with polyethylene glycol 400. The findings suggest that polyethylene glycol 400 in contrast to glycerol and propylene glycol has the potential of increasing the vehicle-skin partition coefficient of oxybenzone when cosmetic products containing such an UV absorber are topically applied to the skin.     

Effect of polyols on polyethylene glycol (PEG)-induced precipitation of proteins: Impact on solubility, stability and conformation

Effect of polyols on the solubility of bovine serum albumin (BSA) in the presence of polyethylene glycols (PEGs) was investigated in order to strengthen the understanding of the observed effects of polyols and PEGs on protein properties in solution. Effect of polyols and/or PEGs on the thermodynamic (conformational) stability of BSA was measured using DSC and circular dichroism (CD). Glucose, sucrose, raffinose, glycerol and sorbitol, all reduced the extent of protein precipitation. Solubility of BSA in the presence of ethylene glycol increased in the case of PEG 1450 and PEG 8000, but was unaffected in the case of PEG 400. DSC studies indicated that smaller PEGs have destabilizing influence on protein structure. CD studies showed that smaller PEGs (ethylene glycol) induce subtle unfolding while stabilizing polyols induce subtle compaction. Results show that, effect of polyols on the apparent solubility of the protein correlates with their effect on the thermodynamic stability of the protein, smaller PEGs are not appropriate for estimating the activity of proteins in saturated solutions, and subtle changes in protein conformation can significantly affect protein precipitation. Though smaller PEGs have weak attractive interactions with protein molecules, perturbation of protein structure by PEGs can be balanced by utilizing appropriate stabilizing solutes.