Form conversion of anhydrous lactose during wet granulation and its effect on compactibility
ABSTRACT The purpose of this study was (a) to evaluate the factors affecting the form conversion of anhydrous lactose to the monohydrate form during wet granulation using water as the granulating agent and (b) study the effect of lactose form conversion on its compaction properties. A two-level full factorial design with two center points was used to evaluate the factors affecting form conversion. The three variables evaluated were percentage of microcrystalline cellulose (low 0 and high 20), water to intragranular solids ratio (low 0.10 and high 0.18) and drying conditions (tray drying and fluid bed drying). The presence of microcrystalline cellulose in the formulation did not provide any benefit in reducing the percent lactose conversion. But, the conversion was significantly reduced by decreasing the amount of water added to the granulation and/or by decreasing the drying time, using a fluid bed dryer compared to a tray dryer. In the second part of the study, complete conversion of the anhydrous lactose to monohydrate was achieved by storing the anhydrous form under 25 degrees C/97% RH for 4 weeks. Physical characterization (compactibility, surface area and surface morphology) was performed on the form converted material and compared to the as received anhydrous lactose. The physical characterization results indicated that even though anhydrous lactose undergoes complete form conversion to monohydrate form under high humidity and/or during wet granulation, it retains its inherent higher as received material compactibility and the BET surface area and porosity of the form converted material are higher than that of the as received anhydrous lactose.
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ABSTRACT: Pellets intended for oral dosing are frequently produced via extrusion/spheronization followed by drying. Typically, the last active process step, i.e., drying, is assumed to have little effect on the final dosage form properties (e.g., dissolution characteristics). Thus, there exist only a few studies of this subject. In the present study, calcium stearate/ibuprofen pellets were used as model system to investigate the impact of the drying conditions. Lipophilic calcium stearate matrix pellets containing 20% ibuprofen were prepared via wet extrusion/spheronization. Subsequently, desiccation, fluid-bed drying, and lyophilization were applied for granulation liquid removal. The impact of these drying techniques on the final pellet properties was evaluated. The in vitro dissolution behavior was dramatically altered by the drying techniques that were considered. The investigated pellets showed drug release rates that varied as much as 100%. As no polymorphic transitions occurred during drying, we focused on two possible explanations: (a) a change in the drug distribution within the pellets and (b) a change in pellet micro-structure (porosity, pore size). The ibuprofen distribution proved to be homogeneous regardless of the drying conditions. Pellet porosity and pore sizes, however, were modified by the drying process. Our results clearly demonstrate that a single process step, such as drying, can play a crucial role in achieving desired pellet properties and release profiles.AAPS PharmSciTech 05/2012; 13(2):686-98. DOI:10.1208/s12249-012-9791-6 · 1.78 Impact Factor
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ABSTRACT: The real (ε') and imaginary (ε″) components of the complex permittivity of anhydrous lactose and microcrystalline cellulose (MCC) under different bulk densities, moisture contents (MCs), and times of hydration (for anhydrous lactose) were measured nondestructively using a microwave resonator sensor operating in the range of 700-800 MHz. Measurements of sensor resonant frequency and conductance allow, through calibration, determination of the complex dielectric properties ε' (relative permittivity) and ε″ (relative dielectric loss) of the test material. Characteristic graphs of ε″ versus ε' - 1 curve for each powder were generated as a function of bulk density and MC. Such data can be used to develop empirical models for the simultaneous in situ measurement of the bulk density and MC of the powders. Unlike MCC, anhydrous lactose is converted to its hydrate form in the presence of moisture, which causes a reduction in the amount of physisorbed and "free" water and a subsequent change in the dielectric properties. For powders such as anhydrous lactose that can form a crystal hydrate in the presence of moisture, a combination of techniques such as vibrational spectroscopy together with microwave resonator measurements are appropriate to characterize, in situ, the physical and chemical properties of the powder.Journal of Pharmaceutical Sciences 07/2011; 100(7):2920-34. DOI:10.1002/jps.22516 · 3.13 Impact Factor
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ABSTRACT: To co-crystallise mannitol and lactose with a view to obtaining crystals with more favourable morphological features than either lactose or mannitol alone, suitable for use as carriers in formulations for dry powder inhalers (DPIs) using simultaneous engineering of lactose-mannitol mixtures. Mannitol and lactose individually and the two sugars with three different ratios were crystallised/co-crystallised using anti-solvent precipitation technique. Obtained crystals were sieved to separate 63-90 μm size fractions and then characterised by size, shape, density and in vitro aerosolisation performance. Solid state of crystallized samples was studied using FT-IR, XRPD and DSC. At unequal ratios of mannitol to lactose, the elongated shape dominated in the crystallisation process. However, lactose exerted an opposite effect to that of mannitol by reducing elongation ratio and increasing the crystals' width and thickness. Crystallised β-lactose showed different anomers compared to commercial lactose (α-lactose monohydrate). Crystallised α-mannitol showed different polymorphic form compared to commercial mannitol (β-mannitol). Crystallised mannitol:lactose showed up to 5 transitions corresponding to α-mannitol, α-lactose monohydrate, β-lactose, 5α-/3β-lactose and 4α-/1β-lactose. In vitro deposition assessments showed that crystallised carriers produced more efficient delivery of salbutamol sulphate compared to formulations containing commercial grade carriers. The simultaneous crystallization of lactose-mannitol can be used as a new approach to improve the performance of DPI formulations.Pharmaceutical Research 04/2012; 29(8):2139-56. DOI:10.1007/s11095-012-0743-3 · 4.74 Impact Factor