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The purpose of the present study was to investigate the effects of molecular weight (MW) of polyvinylpyrrolidone (PVP) on glass transition and crystallization of sucrose. Thus, sucrose was co-lyophilized with 2.5 and 5.0% w/w PVP of different molecular weights, which were characterized using gel permeation chromatography. Freeze drying was carried out for 48 h at a shelf temperature of -40 degrees C and a pressure of about 36 Pa. The samples were then dried in a vacuum oven at 24 degrees C for 12 h before drying for a further 12 h at 40 degrees C. Differential scanning calorimetry (DSC) was employed to measure the glass transition temperature (Tg), dynamic crystallization temperature (Tc) and isothermal crystallization induction time (tc) at 85 degrees C of sucrose. Isothermal water vapour sorption of each sample was also measured at different relative humidities. Tg values of sucrose varied from 48.3+/-0.8 degrees C for freeze-dried (FD) sucrose alone to 58.8+/-0.8 degrees C for the mixture containing 5.0% PVP of nominal MW 300 K. PVP increased sucrose T(g) significantly (ANOVA P<0.05). Although there was no significant difference (P>0.05) in Tg of the mixtures containing 2.5% w/w PVP of different MW, samples with 5.0% PVP of MW 300 K produced a significantly higher (P<0.05) Tg than the other mixtures. All mixtures were shown to possess higher (P<0.01) Tc than FD sucrose alone, which exhibited a T(c) of approximately 85 degrees C. PVP of MW 300 K consistently induced a significantly (P<0.05) higher Tc of sucrose than PVP of smaller MW. Increasing PVP concentration from 2.5 to 5.0% also resulted in a substantial increase in sucrose Tc. Using isothermal water vapour absorption, sucrose tc was found to increase up to over 10 times when it was co-lyophilized with 2.5% PVP, the actual value of tc being dependent upon the MW of the PVP. For example, PVP of MW 300 K resulted in a sucrose tc at 85 degrees C (89.1-95.6 min), which was approximately seven times higher than that of 2.5% PVP of MW 24 or 40 K. A longer tc of sucrose was also observed for mixtures containing PVP of MW 300 K than when sucrose was mixed with PVP of smaller MW. Thus the effect of PVP on sucrose Tg, Tc and tc was found to be dependent upon MW. PVP of higher MW was more efficient in inhibiting sucrose crystallization and by stabilizing glassy structures of the sugar, these polymers may improve the stability of co-lyophilized proteins and peptides.

The aim of this study was to investigate the dispersion and deaggregation of a model drug, salbutamol sulphate (SS), using lactose, mannitol or sorbitol as coarse and fine carriers. Binary and tertiary formulations containing micronised salbutamol sulphate (SS) and sieved (63-90 microm) coarse sugar crystals or salbutamol sulphate (SS) with a mixture of coarse and fine sugar particles were prepared. Factorial design was employed to investigate the effects of three variables, i.e. the chemical entity of the coarse sugar carrier, the chemical entity of the fine sugar and the concentration of fine sugar, on the dispersion and deaggregation of salbutamol sulphate after aerosolisation at 60 l/min via a Rotahaler(R) into a twin stage liquid impinger (TSI). The binary formulations containing the different sugar entities produced differences in the fine (<6.4 microm) particle fraction (FPF) of SS in a decreasing order of mannitol >sorbitol >lactose, but failed to produce efficient dispersion of SS since the FPF was <10%. Adding fine sugar particles and increasing their concentration to the binary mixtures generally resulted in an increase in the FPF of salbutamol sulphate. The chemical nature of the fine carriers was found to play a less important role in determining respirable fraction of the drug than the coarse carriers. In conclusion, other sugars such as mannitol or sorbitol, besides lactose, may be employed as coarse and/or fine carriers for incorporation into dry powder aerosol formulations to increase FPF.

Alpha-lactose monohydrate was prepared to have different morphological features but with similar particle size. The crystal shape and surface smoothness of lactose were quantified by a number of shape descriptors and these were supported qualitatively by the visual examination of scanning electron (SE) micrographs of the crystals. All batches of lactose were subjected to a similar history of processing before blending separately with micronised salbutamol sulphate (SS) in a ratio of 67.5:1, w/w, using similar procedures. In vitro deposition of SS from these formulations was investigated after aerosolisation of the formulations at 60 l min(-1) via the Rotahaler and the Cyclohaler into a twin stage liquid impinger. The formulations prepared using the different batches of lactose produced different deposition profiles of SS. The fine particle (< 6.4 microm) fraction (FPF) of aerosolised SS varied from 12.6 +/- 2.4 to 25.6 +/- 1.5% after aerosolisation from the Cyclohaler whilst it changed from 15.0 +/- 2.2 to 24.4 +/- 0.8% after aerosolisation from the Rotahaler. The fine particle dose (FPD) and dispersibility of SS followed a similar trend to the change in the FPF of the drug. No significant difference (ANOVA P > 0.05) was observed for the deposition profiles of SS after aerosolisation from the Rotahaler and the Cyclohaler. The FPF and dispersibility of SS increased with either the surface smoothness (P < 0.01) or elongation ratio (P < 0.01) of lactose crystals. The t-ratio values of FPF and dispersibility of SS generated by changes in the surface smoothness were similar to those resulting from changes in elongation ratio. Increasing either the surface smoothness or the elongation ratio of lactose crystals will increase the potentially respirable fraction of SS from dry powder formulations for inhalation.

Dry powder formulations for inhalation usually comprise a mixture of coarse lactose (CL), employed as a carrier, and micronized drug. It was the aim of this study to determine the effects of fine lactose (FL), blended as a tertiary component on the mixing homogeneity and dispersibility of a model hydrophobic drug, beclomethasone dipropionate (BDP). BDP particles (volume median diameter (VMD) 4.6 microm) existed mainly as agglomerates, the majority of which were not dispersed into primary particles after aerosolization at a high shear force (4.7 psi). The resultant particle size distribution of BDP was multi-modal with VMD varying between 4.7 and 30.2 microm. Ternary interactive mixtures were prepared to consist of CL, FL and BDP with a fixed ratio of lactose to BDP of 67.5:1 w/w, but two concentrations of FL, i.e. 2.5 and 5%, w/w. The mixing was carried out using different sequences of adding the three components for two mixing times (15 and 60 min). Binary mixtures composed of CL and BDP were prepared for both mixing times as the controls, and these exhibited a coefficient of variation (COV) in BDP content <= 5%. Addition of FL to the binary formulations greatly reduced the content uniformity of BDP if the final powder were prepared by first mixing CL with FL before mixing with the drug (COV>20%, after mixing for 15 min). However, the mixtures, prepared using other mixing sequences, had a similar uniformity of BDP content to the binary mixtures. All ternary mixtures containing 2.5% FL consistently produced a significantly higher (ANOVA P<0.01) fine particle fraction (FPF, 3.1--6.1%) and fine particle dose (FPD, 13.6--30.1 microg) of BDP than the binary mixtures (FPF, 0.3-0.4%; FPD, 1.6-2.1 microg) after aerosolization at 60 l min(-1) via a Rotahaler into a twin stage liquid impinger. The mixing sequences exerted a significant (P<0.05) effect on the dispersion and deaggregation of BDP from the formulations prepared using a mixing time of 15 min but such an effect disappeared when the mixing time was lengthened to 60 min. The dispersibility of BDP was always higher from the ternary mixtures than from the binary mixtures. BDP delivery from dry powder inhalers was improved markedly by adding FL to the formulation, without substantial reduction in the content uniformity of the drug.

Five different grades of lactose namely, anhydrous lactose, medium lactose, regular lactose, lactose crystals and foremost lactose were fractionated under similar conditions to obtain a size range of 63-90 microm and were characterised using laser diffraction and time-of-flight particle sizing techniques, scanning electron microscopy, optical microscopy image analysis, thermal gravimetric analysis and differential scanning calorimetry. Each of these lactose fractions were then blended separately with micronised salbutamol sulphate in a ratio of 67.5:1 (w/w). The mixing uniformity and percentage recovery of salbutamol sulphate in the powder blends were analysed using a validated HPLC method. The deposition profiles of the drug were determined using a 5-stage liquid impinger after aerosolisation at 60 l min(-1) via a Rotahaler. Despite the identical processing conditions, the lactose fractions were shown to differ in particle size, size distribution and concentrations of fine particles. The particles from each fraction also exhibited different surface textures and dissimilar DSC thermograms. However, all the blends of the lactose with salbutamol sulphate were found to have a relatively high uniformity of salbutamol sulphate content, as suggested by a coefficient of variation of less than 3.2%. Anhydrous and medium lactose produced a more efficient delivery of salbutamol sulphate when aerosolised from the Rotahaler in comparison to other grades of lactose. For example, the fine particle fraction (FPF) and fine particle dose (FPD) of drug from formulations containing anhydrous lactose were 13.4+/-4.2% and 57.3+/-17.6 microg, respectively, which were approximately two times higher than the respective values of the formulation containing regular lactose. Medium lactose resulted in drug FPF (7. 9+/-2.7%) and FPD (32.4+/-11.8 microg), which were significantly (ANOVA P<0.05) higher than the same parameters obtained using lactose crystals, foremost lactose and regular lactose. More efficient drug delivery from anhydrous lactose may be partly attributed to the relatively higher concentration of fine lactose in this grade of carrier, although it showed a rougher surface than the other grades of lactose. However, the relatively high FPF of the drug from medium lactose may have been due to the relatively small mean particle size and smooth surface of the particles. Therefore, the source and grade of lactose may have a substantial effect on drug delivery from dry powder inhaler formulations and care should be taken in establishing appropriate quality control parameters when selecting an appropriate grade of carrier.

Ternary mixtures composed of coarse lactose (CL) (90.8 microm), salbutamol sulphate (SS) (5.8 microm) and either micronised lactose (ML) (5 microm) or intermediate sized lactose (IML) (15.9 microm) in a ratio of 66.5:1:1 w/w were prepared using different mixing sequences of the various components. In addition, a binary mixture composed of CL and SS (67.5:1 w/w) was also prepared as the control. The in vitro deposition of SS was measured using a twin stage impinger after aerosolisation at 60 and 90 l min-1 via a Rotahaler. The aerodynamic particle size distribution of both the aerosolised SS and lactose was further analysed using an Andersen cascade impactor at 60 l min-1. All ternary mixtures produced a significantly higher (analysis of variance, P<0.01) fine particle fraction (FPF) and fine particle dose (FPD) of SS than the control after aerosolisation at either 60 or 90 l min-1. Formulations containing the ML produced significantly (P<0.05) higher FPF and FPD of SS than those containing the IML at both aerosolisation flow rates. Different mixing sequences were also shown to result in different deposition profiles of both SS and lactose after aerosolisation of the ternary mixtures containing ML at 60 l min-1. The formulation prepared by first blending ML with CL before mixing with SS produced a higher FPF and FPD of SS but a lower FPF of lactose than the same formulation in terms of composition but prepared using different mixing orders of the three components. In contrast, the formulations containing IML produced a similar deposition profile to SS, regardless of the mixing sequences, and so did the formulations containing ML aerosolised at 90 l min-1. These results suggest that the effect of mixing sequences on drug deposition may become more prominent at lower aerosolisation flow rates and by reducing the size of any added fine lactose.