Deformation Potential and Tensile Strength of Tablets of a Dry Granulated Formulation.

The increase in solid fraction (SF) of a packed granule bed with pressure applied during the in-die compression process results in an evolution of the tablet's matrix and mechanical strength. In this case study, the tensile strength (TS) of a dry granulated microcrystalline cellulose (MCC)/mannitol (MNT)-based formulation was modeled in light of the deformation potential, ∆ (tablet SF - initial granule bed SF). Results showed that the TS of tablets linearly decreased as SF of granules (produced as mini-tablets of an ibuprofen formulation) increased. The formulated granules achieved a measurable tablet strength at a slightly lower critical deformation potential (∆c) than the pure MCC granules. Beyond ∆c, tablet TS increased almost linearly as the deformation potential increased, and the rate was higher for tablets with higher SF. Compared to the simple MCC system, the granules of the MCC/MNT-based formulation were weaker, and TS of tablets increased with deformation potential at a lower rate.

Dropwise Additive Manufacturing of Pharmaceutical Products Using Particle Suspensions.

The principal method of drug delivery is by oral solid doses, the production of which often necessitates multiple post-crystallization unit operations to ensure content uniformity or enhance bioavailability. As an alternative to conventional dose production methods, applications of additive manufacturing technologies based on solvent- or melt-based formulations have demonstrated the potential for improvements to process efficiency, flexibility, and dosing precision. Here we explore the use of particulate suspensions in a dropwise additive manufacturing process as a method for dosing active ingredients in crystalline form, which may be difficult to achieve via powder processing due to poor flow properties. By employing a fluid-based method, powder flow issues are alleviated and adaptation of the process to new particles/crystals is facilitated by dimensional analysis. In this work, a feasibility study was conducted using 4 active ingredient powders, each with non-ideal particle properties, and 2 carrier fluids, in which the active ingredient does not dissolve, to formulate suspensions for dose manufacturing; drug products were analyzed to show reproducibility of dosing and to assess preservation of particle size through the process. Performance across particle types is affected by particle size and shape, and is related through effects on the rheological properties of the formulation.

Tablet Compression Force as a Process Analytical Technology (PAT): 100% Inspection and Control of Tablet Weight Uniformity.

The modern rotary pharmaceutical tablet press is capable of accepting or rejecting individual tablets based on the measured compression force of the tablet. Because during steady operation, each tablet is compressed to the same thickness, a larger compression force implies a heavier tablet. Tablets that are too heavy likely contain more than the desired content of drug substance. The measured compression force thus becomes an important input to the overall control strategy, and variability in the compression force from one tablet to the next corresponds directly with the uniformity of dosage units. This provides an extraordinary opportunity to use the instantaneous compression force signal as a process analytical technology to make product collection decisions on every individual tablet. Only 1 question requires investigation: how to set the main compression force limits to achieve the desired tablet weights? In this work, a small-scale characterization method and associated mathematical model are developed to answer this question.

Reproducibility of the Measurement of Bulk/Tapped Density of Pharmaceutical Powders Between Pharmaceutical Laboratories.

The bulk properties of a powder are dependent on the preparation, treatment, and storage of the sample, that is, how it was handled. The particles can be packed to have a range of bulk densities and, moreover, the slightest disturbance of the powder bed may result in a changed bulk density. Thus, the bulk density of a powder is often difficult to measure with good reproducibility and, in reporting the results, it is essential to specify how the determination was made. In this article, we measured the bulk density, tapped density, and calculated the Hausner ratio of commonly used excipients with similar tapped density testers and followed the United States Pharmacopeia 30-National Formulary 25-S1 testing procedure. Based on the analysis, within lot and lot-to-lot variability and the relative errors for bulk density, tapped density, and Hausner ratio were found to be acceptable. Lot-to-lot differences were generally not measurable using this test as they were found to be within the variability of the test. The results also indicated that there was no statistically significant bias between sites for tapped density and Hausner ratio, but there was a marginally significant bias in the bulk density data set.

Assessment of Intragranular and Extragranular Fracture in the Development of Tablet Tensile Strength.

When a tablet is compacted from deformable granules and then broken, the fracture plane may cleave granules in 2 (intragranular fracture) or separate neighboring granules (extragranular fracture). In this study, a novel method was developed to quantify the extent of intragranular versus extragranular fracture by compacting tablets from multicolored ideal granules and evaluating fracture surfaces. The proportions of intragranular and extragranular fracture were quantified and modeled in light of a new metric; the deformation potential, Δ, reflecting the solid fraction increase as an initial granule bed is compressed into a final tablet. Results show that a measurable tablet strength is achieved at Δ > 0.18, but intragranular fracture is not observed until Δ > 0.21. At very large Δ, tablets experience almost exclusively intragranular fracture, yet the tablet tensile strength is considerably lower than that of a tablet compacted from raw powders versus precompacted granules. Thus, secondary compaction of granules appears to weaken the granule matrix, leading to reduced tablet tensile strength even in the presence of strong extragranular bonding.

Note on the Use of Diametrical Compression to Determine Tablet Tensile Strength.

The diametrical compression (DC) test, as defined in United States Pharmacopeia <1217> and in American Society for Testing and Materials testing standard D 3967, has been used extensively to derive the tensile strength (TS) of pharmaceutical tablets from the measured breaking force. DC-derived TSs provide a good approach to measuring the consistency of tablet mechanical properties from one batch to the next. For these quality control type applications, method precision is required, but accuracy is not. In addition, DC has been used to calibrate parameters of the Druker Prager Cap model, a yield criterion expressing the failure of a powder compact under arbitrary 3D loading conditions. For this application, the DC method must not only provide suitable precision but also provide accuracy. In this work, we explore the accuracy of the DC method by comparing TS results to those of the 3-point bend test method (also defined in United States Pharmacopeia <1217>). We conclude that the true TS of a powder compact is approximately double the DC-derived value. Although historical literature assumes that tablets fracture under tension along the centerline of the tablet, analysis of the stress state suggests that tablets are likely to fracture under shear. The impact of this ∼50% error should be considered when accuracy of the TS result is required.

A first-principles model for prediction of product dose uniformity based on drug substance particle size distribution.

The unit dose uniformity (UDU) of low-dose drug products can be affected by active pharmaceutical ingredient (API) particle size. UDU relative standard deviation increases as the fraction of large API particles increases and/or as the unit dose decreases. Control of API particle size has traditionally been based on the empirical relationship of d(90) and/or d(50) statistics to drug product uniformity. Several articles have been written that have identified a theoretical relationship between these particle size statistics, dose, and the probability of meeting US Pharmacopeial UDU testing criteria (Huang CY, Ku S. 2010. Int J Pharm 383:70-80; Rohrs B, Amidon G, Meury R, Secreast P, King H, Skoug C. 2006. J Pharm Sci 95(5):1049-1059; Huang CY, Ku S. 2010. J Pharm Sci 99:4351-4362; Yalkowsky SH, Bolton S. 1990. Pharm Res 7(9):962-966). However, these theoretical relationships assume a fixed shape for the API particle size distribution (PSD, i.e., lognormal) and do not account for changes in the distribution shape. A more rigorous method for predicting the effect of a given PSD on UDU is to evaluate the contribution of individual particle size bins on UDU variability. The latter approach is taken in this work, and the derivation reveals that the individual contribution of particles size bins can be expressed completely in terms of a single-particle-size statistic, D[6,3]. D[6,3] is therefore a valid predictor of UDU, regardless of the shape of the PSD (e.g., multimodal) and can form the basis of a particle size control strategy for low-dose drug products.

Using a novel multicompartment dissolution system to predict the effect of gastric pH on the oral absorption of weak bases with poor intrinsic solubility.

A novel multicompartment dissolution system was developed by modifying a conventional six-vessel United States Pharmacopoeia dissolution system to study the dissolution and possible precipitation of poorly soluble weak bases after oral administration. The modified system includes a "gastric" compartment, an "intestinal" compartment, an "absorption" compartment, and a reservoir to simulate the dissolution and absorption in the gastrointestinal tract. Dissolution profiles of 50-mg dipyridamole (pK(a) 6.0, 12.5) tablet (2 * 25 mg Persantine tablets), 25- and 50-mg cinnarizine (pK(a) 1.95, 7.5) powders, which are poorly soluble weak bases, were generated in the system using dissolution medium with different pHs in the "gastric" compartment. The in vitro dissolution results were compared with the in vivo oral exposure data in humans. For both dipyridamole and cinnarizine, the in vitro dissolution using the multicompartment system was able to predict the pH effect on oral exposure. The results from the multicompartment system are more closely correlated with the in vivo data, compared with that from the conventional dissolution test. The system showed that although both dipyridamole and cinnarizine completely dissolved in the gastric compartment at lower pH, approximately 36% (at 25-mg dose) and 40% (at 50-mg dose) of cinnarizine precipitated in the "intestinal" compartment whereas the precipitation of dipyridamole was <10% of the initial dose. The difference in the amount "absorbed" between these two compounds in vitro is therefore primarily attributed to the precipitation potential, although no in vivo data are available to confirm this result. The difference in the amount precipitated may be explained by the lower solubility and consequently higher degree of supersaturation of cinnarizine in the "intestinal" compartment.

In situ monitoring of wet granulation using online X-ray powder diffraction.

PURPOSE: Polymorphic transformations during the wet granulation of a metastable polymorph of flufenamic acid were monitored in situ using online X-ray powder diffraction. The resulting data were used in testing a proposed process induced transformation rate model, which allows the extent and occurrence of polymorphic transformations during wet granulation to be controlled by adjusting the granulation time. METHODS: A small-scale, top mixing granulator was designed for compatibility with novel X-ray powder diffraction equipment (available from X-Ray Optical Systems of East Greenbush, NY). RESULTS: The unique polycapillary optic and X-ray source allowed the transformation of the metastable to the stable polymorph to be followed during the granulation. Following a diffraction peak each for the metastable and stable forms demonstrated that polymorphic transformations during the wetting phase of granulation follow the trends predicted by the model. CONCLUSIONS: The advanced online monitoring may allow real-time control of the process by the adjustment of process parameters, such as granulation time, and clearly qualifies as a PAT (process analytical technology).