Surface Modification of lactose carrier particles using a fluid bed coater to improve fine particle fraction for dry powder inhalers.

Surface roughness of carrier particles can impact dry powder inhaler (DPI) performance. There are opposing views on the effect of roughness on DPI performance. Hence, a systematic approach is needed to modify carrier surfaces and evaluate the impact on drug delivery. Carrier particle surfaces were modified by fluid bed coating with saturated lactose containing micronized lactose of different sizes (2, 5 and 8 µm) and coated to different levels (20, 40, 60 and 80%). Their drug delivery performance was assessed by the fine particle fraction (FPF). Roughness parameters, mean arithmetic roughness (Ra) and arithmetic mean height (Sa), of the carrier particles, were also evaluated using optical profilometry and scanning laser microscopy. Generally, particles of higher Ra had higher FPF. Higher Sa resulted in higher FPF only for particles with 60 and 80% coat levels. Reduced contact surface area between the drug particle and rougher carrier particle resulted in easier drug detachment during aerosolization. The 5 µm micronized lactose produced optimal carrier particles with respect to FPF and surface roughness. The study highlighted that with the ideal particles for surface roughening and coating level, surface roughening could be efficiently achieved by fluid bed coating for superior DPI performance.

Investigation on the effect of roller compaction on paracetamol.

Roller compaction is a popular dry granulation method that has been associated with loss of tabletability. In this study, the effect of roller compaction on a model brittle elastic material, paracetamol, was examined. Roller compaction of paracetamol was carried out at three roll force to examine the effects of roll force on the tablet compaction properties. Paracetamol granules consisting of small fragmented crystals were created through the process of roller compaction. A compaction simulator was used to produce tablets from a sieved fraction of roller compacted paracetamol and non-roller compacted paracetamol. Despite the higher elastic energy to plastic energy ratio observed with tablets produced from roller compacted granules of higher forces, the table tensile strength obtained was higher with a lower capping coefficient. At the same time, tablet elastic recovery was found to be lower for tablets produced using roller compacted paracetamol granules. Prefragmentation during roller compaction process helped to reduce the energy required for fragmentation during tablet compaction, increasing the energy available for bond formation. Roller compaction of brittle elastic materials may be a viable option for improving tablet tensile strength and reducing tablet capping.

Effects of Particle Surface Roughness on In-Die Flow and Tableting Behavior of Lactose.

Particle rearrangement takes place during the initial phase of tablet compaction. In this study, rough lactose particles were prepared by roller compaction, and their surface roughness modified by partial surface dissolution using a fluidized bed processor. Flow characteristics of the particles were determined using various flow methods, and their compaction characteristics studied using a compaction simulator with punches of different geometry and compaction pressure. Rougher particles demonstrated poorer compressibility and powder flow due to the higher interparticulate frictional forces required for particle movement. Rearrangement energy during tablet compaction was found to be correlated with compressibility (R2 = 0.92) and increased with surface roughness of the particles. Particle rearrangement was found to be dependent on interparticulate frictional forces, which could be measured using FT4 powder rheometer variable flow rate test and compressibility test. Plastic energy decreased as a result of the increased rearrangement energy requirements. Decrease in tensile strength as a result of decrease in plastic energy was not significantly different. Roller-compacted lactose particles produced tablets of higher tensile strength than crystalline lactose because of prefragmentation of the crystalline structure during roller compaction.

Dissolution of fine particle fraction from truncated Anderson cascade impactor with an enhancer cell.

Dissolution testing for inhalers were previously conducted either on unfractionated drug-carrier powders or drug of specific aerodynamic particle size. In this study, the collection of the full fine particle fraction (FPF) was attempted on a single stage. Capsules containing 30 mg of 2% salbutamol sulfate (SS) was tested to have a FPF of 9 ±â€¯1% using the full set of Andersen cascade impactor (ACI) and a modified Rotahaler® capable of achieving 4.0 kPa pressure drop at 60 L/min air flow rate. A truncated ACI comprising the USP throat, pre-separator, stage 0, stage 4, stage F, polytetrafluoroethylene funnel (TF) and small collection plate (sCP) was found to be capable of achieving a FPF of 9% collected on TF and sCP. An adhesive tape was used to collect the FPF from the TF and sCP and held in place by an enhancer cell in a 200 mL round bottom vessel containing 50 mL Gamble's solution with 0.2 v/v, % Tween 80. Dissolution testing of SS and Seretide® showed burst release of SS and salmeterol while sustained release of fluticasone. This study demonstrated a reproducible method which may be used for evaluation of the full FPF of orally inhaled products.

Powder Flow Testing: Judicious Choice of Test Methods.

Flow property of pharmaceutical powders can be assessed by various flow testers and test methods. In this study, eight commercially available lactose grades were sourced and tested for angles of repose, tapping studies, shear cell measurements, stirred powder rheometry, and avalanching powder measurements. The relationships between various flow parameters and particle size were analyzed. Deviations from the general trend could be attributed to either the insensitivity of the test or differences in particle shape. The basic flowability energy of the powder rheometer was unable to reconcile the effects of shape and particle size on powder flowability. Avalanche time of the revolving drum powder analyzer and angle of repose exhibited good correlation with each other (r = 0.92) but experienced poor resolution for samples of smaller particle sizes due to powder cohesiveness and the propensity for agglomerative flow. Flow test parameters could be categorized into three broad types, based on their relationship with particle size: (i) linear relationship, (ii) test parameter more sensitive to smaller sized particles, and (iii) test parameter more sensitive to larger sized particles. Choice of test parameters used to represent powder flow should be dependent on the sensitivity of the selected flow test methods to the sample types.

Investigation of the milling capabilities of the F10 Fine Grind mill using Box-Behnken designs.

Size reduction or milling of the active is often the first processing step in the design of a dosage form. The ability of a mill to convert coarse crystals into the target size and size distribution efficiently is highly desirable as the quality of the final pharmaceutical product after processing is often still dependent on the dimensional attributes of its component constituents. The F10 Fine Grind mill is a mechanical impact mill designed to produce unimodal mid-size particles by utilizing a single-pass two-stage size reduction process for fine grinding of raw materials needed in secondary processing. Box-Behnken designs were used to investigate the effects of various mill variables (impeller, blower and feeder speeds and screen aperture size) on the milling of coarse crystals. Response variables included the particle size parameters (D10, D50 and D90), span and milling rate. Milled particles in the size range of 5-200 µm, with D50 ranging from 15 to 60 µm, were produced. The impeller and feeder speeds were the most critical factors influencing the particle size and milling rate, respectively. Size distributions of milled particles were better described by their goodness-of-fit to a log-normal distribution (i.e. unimodality) rather than span. Milled particles with symmetrical unimodal distributions were obtained when the screen aperture size was close to the median diameter of coarse particles employed. The capacity for high throughput milling of particles to a mid-size range, which is intermediate between conventional mechanical impact mills and air jet mills, was demonstrated in the F10 mill. Prediction models from the Box-Behnken designs will aid in providing a better guide to the milling process and milled product characteristics.