Aktham Aburub

BASELINE STUDIES OF THE CLAY MINERALS SOCIETY SOURCE CLAYS: SPECIFIC SURFACE AREA BY THE BRUNAUER EMMETT TELLER (BET) METHOD

Specific surface area measurements of The Clay Minerals Society source clays were made by the Brunauer, Emmett and Teller (BET) method of adsorption of nitrogen gas. Two replicate measurements of specific surface area were performed for each source clay. All pair values were within 3%, which is very good agreement for this type of measurement.

Physical Stability of Salts of Weak Bases in the Solid-State

When selecting the physical form of an active pharmaceutical substance, there is often a question of when a molecules pKa renders it too low for salt formation and formulation into a product that will be sufficiently physically stable to provide adequate shelf life. In the paper, a graph is provided that tabulates pKa values of active pharmaceuticals versus the salt or free base form that was chosen to be developed as an orally administered drug product. Tabulation of the data provides insight into where, if any, practical cutoff exists, under which salt formation should not be considered. Specific examples of disproportionation reactions are reviewed and are described in light of the concepts of pH maximum, pH microenvironment, and Gibbs free energy to gain further insight into when such reactions become favorable. The driving force for disproportionation reactions is substantially greater than that for polymorphic form conversion, and as a consequence, its probability of occurring in the solid-state is much greater when formulated in favorable microenvironments. Factors that influence the reaction rate are examined. It is concluded that each salt should be evaluated on the merit of its physical properties and often the most soluble salt will not be ones best choice. Unfortunately, compounds that stand to benefit the most from salt formation due to their exceptionally low intrinsic solubility are the ones that will be most likely to disproportionate if their pKa is relatively low.

Use of Compaction Energetics for Understanding Particle Deformation Mechanism

A primary goal of the current work was to examine the potential use of compaction energetics as a tool to predict particle deformation mechanism. Three deformation models, namely, those developed by Heckel, Walker, and Gurnham, were first used to evaluate the deformation mechanisms of 11 commonly used excipients. To complement the information gained from the deformation models, the mechanical energy used in tablet formation was then examined. It has been found that the sum of the work in the compression and decompression phases (plastic work) is a relatively good indicator of a materials plasticity. Conclusions based on this indicator regarding deformation mechanism for the different diluents used were in good agreement with those obtained from the different deformation models studied.

Weak bases and formation of a less soluble lauryl sulfate salt/complex in sodium lauryl sulfate (SLS) containing media.

This work reports on the solubility of two weakly basic model compounds in media containing sodium lauryl sulfate (SLS). Results clearly show that the presence of SLS in the media (e.g. simulated gastric fluid or dissolution media) can result in an underestimation of solubility of some weak bases. We systematically study this phenomenon and provide evidence (chromatography and pXRD) for the first time that the decrease in solubility is likely due to formation of a less soluble salt/complex between the protonated form of the weak base and lauryl sulfate anion.

Interpreting deformation behavior in pharmaceutical materials using multiple consolidation models and compaction energetics

Tableting behavior is often characterized using qualitative analyses of compactibility and compressibility measurements. More quantitative methods use consolidation models to estimate parameters indicative of the predominating deformation mechanism exhibited by a material. It will be shown that a concerted approach, using multiple consolidation models and mechanical energy analysis, presents a more reliable way of evaluating the relative plasticity of pharmaceutical materials and identifying complicating behaviors. Force versus displacement data for compact formation, porosity versus pressure and tensile strength data for ejected compacts were collected with a single instrument. The porosity and tensile strength data were analyzed using two relatively new models and the results were compared to three more classical models. Additionally, the mechanical work measurements were used to interpret the consolidation model predictions. Although the individual models are susceptible to a number of errors, complications and invalid assumptions, confidence can be gained when diverse models provide similar predictions. Disagreement between the model predictions can be taken as a sign of atypical behavior that should be further investigated by looking at the material’s mechanical energetics. Finally, the use of work energy associated with compression and decompression as an initial measure of plasticity is supported.

Quantitative mineralogical properties (morphology-chemistry-structure) of pharmaceutical grade kaolinites and recommendations to regulatory agencies.

The physical and chemical characteristics of kaolinite (kaolin) may be variable, and minor amounts of other clay minerals, nonclay minerals, and other impurities may affect the properties of kaolinites. Thus specific technical properties of pharmaceutical grade kaolinites become very important because these clays are used in medical applications, e.g., as pharmaceutical excipients, and will be consumed by humans. Seven pharmaceutical grade kaolinite specimens were used in this study: K1004, KA105, 2242-01, K2-500, Acros, Acros-mono, and KX0007-1. In addition, two kaolinites from the Clay Minerals Society Source Clays, KGa-1b and KGa-2, were used for comparison purposes. The Acros-mono and 2242-01 kaolinites contained minor amounts of illite, which was demonstrated both compositionally and structurally by using inductively coupled plasma spectroscopy and powder X-ray diffraction. The KX0007-1 kaolinite powder was found to be heavily contaminated with quartz, cristobalite, and alunite. Crystal structure computations also showed excess Si in its tetrahedral site, and the mineral no longer has the typical kaolinite crystal structure. These widely-used industrial standards should be quantitatively characterized morphologically, compositionally, and structurally. Results of the mineralogical characteristics should be clearly labeled on the pharmaceutical grade kaolinites and reported to the relevant regulatory agencies.

Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [13C8]-evacetrapib as a tracer

This open‐label, single‐period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130‐mg evacetrapib oral dose and 4‐h intravenous (IV) infusion of 175 µg [13C8]‐evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [13C8]‐evacetrapib using high‐performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration‐time curve (AUC) from zero to infinity (AUC[0‐∞]) and to the last measureable concentration (AUC[0‐tlast]), were calculated. Bioavailability was calculated as the ratio of least‐squares geometric mean of dose‐normalized AUC (oral : IV) and corresponding 90% confidence interval (CI). Bioavailability of evacetrapib was 44.8% (90% CI: 42.2–47.6%) for AUC(0‐∞) and 44.3% (90% CI: 41.8–46.9%) for AUC(0‐tlast). Evacetrapib was well tolerated with no reports of clinically significant safety assessment findings. This is among the first studies to estimate absolute bioavailability using simultaneous administration of an unlabeled oral dose with a 13C‐labeled IV microdose tracer at about 1/1000th the oral dose, with measurement in the pg/mL range. This approach is beneficial for poorly soluble drugs, does not require additional toxicology studies, does not change oral dose pharmacokinetics, and ultimately gives researchers another tool to evaluate absolute bioavailability.

Analysis of magnesium from magnesium stearate in pharmaceutical tablet formulations using hydrophilic interaction liquid chromatography with nano quantity analyte detection

This study demonstrates the use of hydrophilic interaction liquid chromatography with a nano quantity analyte detector for the retention, separation and detection of magnesium from magnesium stearate in tablet formulations for a drug product formulation blend containing a hydrochloride salt of a weakly basic compound as the active ingredient. The nano quantity analyte detector can provide direct detection of inactive excipients and inorganic salts lacking ultraviolet chromophores, as well as, all non-volatile compounds. The separation was accomplished using a SeQuant ZIC-HILIC column and mobile phase consisting of 32.5:32.5:35 of acetone/methanol/ammonium formate buffer (150 mM, pH 4.5). Common validation parameters were evaluated to assess the methods quantitative potential for magnesium (from magnesium stearate) including: linearity, accuracy, specificity, solution stability, repeatability, and intermediate precision. Overall, the method described in this report proved to be very robust and represents a novel technique to conveniently separate and detect magnesium from magnesium stearate in pharmaceutical preparations both quickly and accurately.

Particle Engineering for Enabling a Formulation Platform Suitable for Manufacturing Low-Dose Tablets by Direct Compression

Maintaining good content uniformity (CU) is a significant challenge for low-dose oral tablets in particular when using direct compression (DC). Using 6 model active pharmaceutical ingredients, we show that a platform DC tablet formulation suitable for developing low-dose API with excellent CU can be developed. This platform formulation is enabled by particle engineering, where an API of interest is loaded in a suitable porous carrier to form a uniform API-carrier composite. Powder properties of such composite particles are dictated by the properties of the carrier, which are insensitive to chemical structure and loading level of the API. Powder flowability, tabletability, tablet friability, and tablet disintegration time are all excellent and only vary within a narrow range among the 6 model APIs. Nearly 100% drug can be released in water from tablets composed of the 6 model APIs. Thus, the approach described here holds the promise for broad application in developing low-dose tablet products using DC possessing excellent CU and other critical quality attributes.

Cosolvency approach for assessing the solubility of drugs in poly(vinylpyrrolidone)

The log-linear cosolvency model was applied for estimating the solubility of four drugs: ritonavir, griseofulvin, itraconazole and ketoconazole in poly(vinylpyrrolidone) (PVP). Cosolvent mixtures consisted of PVP mixed in different proportions with N-ethylpyrrolidone, which served as the monomeric analogue of the repeating unit of the polymer. Solubility in the monomer-polymer mixtures was determined by HPLC. As the configuration of the solvating unit in the solvent mixture changed from entirely monomeric to increasingly polymeric, the solubility of the drugs decreased in a fashion that follows the log-linear cosolvency model. The linear relationship was used to obtain estimates for the solubility of the drugs in the different grades of PVP. The solubility of the drugs in PVP is low (from <1% to ∼15% w/w). Among the set of drug solutes, ritonavir exhibited the highest solubility in PVP (w/w). Mixing with the monomer is most favorable for griseofulvin among the four drugs. However, the detrimental effect of polymerization on its solubility is more pronounced than for ritonavir. The mixing of itraconazole with the monomer is more favorable than the mixing of ketoconazole. However, despite the molecular similarity between ketaconazole and itraconazole, the solubility of the latter is particularly affected by the polymeric configuration of the solvating unit, to the point of exhibiting differences in solubility resulting from the chain length of the grade of PVP used. The log-linear cosolvency model is a useful tool for estimating the solubility of the drugs in the polymer at room temperature, while providing quantitative information on the differences in mixing behavior of the four model compounds.