The Role of Titanium Dioxide (E171) and the Requirements for Replacement Materials in Oral Solid Dosage Forms: An IQ Consortium Working Group Review.

Titanium dioxide (in the form of E171) is a ubiquitous excipient in tablets and capsules for oral use. In the coating of a tablet or in the shell of a capsule the material disperses visible and UV light so that the contents are protected from the effects of light, and the patient or caregiver cannot see the contents within. It facilitates elegant methods of identification for oral solid dosage forms, thus aiding in the battle against counterfeit products. Titanium dioxide ensures homogeneity of appearance from batch to batch fostering patient confidence. The ability of commercial titanium dioxide to disperse light is a function of the natural properties of the anatase polymorph of titanium dioxide, and the manufacturing processes used to produce the material utilized in pharmaceuticals. In some jurisdictions E171 is being considered for removal from pharmaceutical products, as a consequence of it being delisted as an approved colorant for foods. At the time of writing, in the view of the authors, no system or material which could address both current and future toxicological concerns of Regulators and the functional needs of the pharmaceutical industry and patients has been identified. This takes into account the assessment of materials such as calcium carbonate, talc, isomalt, starch and calcium phosphates. In this paper an IQ Consortium team outlines the properties of titanium dioxide and criteria to which new replacement materials should be held.

Data-driven approach to mitigate quality impact of hygroscopic pharmaceutical raw materials throughout the supply chain.

The challenges of working with hygroscopic pharmaceutical raw materials can have a significant impact on the industry's ability to make high-quality medicines. In order to mitigate the impact to the manufacturing process or product quality it is critical to understand the hygroscopicity of the raw materials across the entire supply chain so that the proper management strategies can be implemented, from the raw material manufacturing to the use of the raw material in the drug manufacturing process. Employing suitable controls protects these materials from physical and chemical changes due to moisture uptake such as caking or hydrolysis. We have developed a fit for purpose and data-driven approach to hygroscopicity classifications of over 200 commonly used chemicals, excipients, media and resins in drug manufacturing processes. Dynamic vapor sorption data is presented with supporting thermal gravimetric analysis and X-ray powder diffraction data where pertinent. Approximately 60% of all raw materials tested were determined to be hygroscopic. Strategies for applying this data to reduce the potential impact of hygroscopic materials on the manufacturing of pharmaceuticals are discussed with examples.

Discovery and in Vivo Evaluation of Macrocyclic Mcl-1 Inhibitors Featuring an α-Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere.

Overexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an α-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of 1, a potent Mcl-1 inhibitor (IC50 = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.

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.

Applications of Powder X-Ray Diffraction in Small Molecule Pharmaceuticals: Achievements and Aspirations.

Since the discovery of X-ray diffraction and its potential to elucidate crystal symmetry, powder X-ray diffraction has found diverse applications in the field of pharmaceutical sciences. This review summarizes significant achievements of the technique during various stages of dosage form development. Improved understanding of the principle involved and development of automated hardware and reliable software have led to increased instrumental sensitivity and improved data analysis. These advances continue to expand the applications of powder X-ray diffraction to emerging research fields such as amorphous systems, mechanistic understanding of phase transformations, and "Quality by Design" in formulation development.

Salt disproportionation: A material science perspective.

While screening the counter-ions for salt selection for an active pharmaceutical substance, there is often an uncertainty about disproportionation of the salt and hence physical stability of the final product formulation to provide adequate shelf life. Several examples of disproportionation reactions are reviewed to explain the concepts of pHmax, microenvironmental pH, and buffering capacity of excipients and APIs to gain mechanistic understanding of disproportionation reaction. Miscellaneous factors responsible for disproportionation are examined. In addition to the dissolution failure due to the formation of less soluble unionized form, various implications of the disproportionation are evaluated with specific examples. During lead optimization and early stages of development, when only a limited amount of material is available, use of predictive tools like mathematical models and model free kinetics to rank order the various counter-ions are discussed in detail. Finally, analytical methods and mitigation strategies are discussed to prevent the disproportionation by detecting it during early stages of drug development.

Maximizing the Impact of Physiologically Based Oral Absorption Modeling and Simulation.

The challenge of bringing innovative medicines to patients in combination with intense competition within the pharmaceutical industry has induced companies to develop quality medicines more efficiently and cost-effectively. State-of-the-art approaches to advance drug development have never been so urgent. One such approach that has been gaining traction within the industry is the application of modeling and simulation. In this commentary, the benefits of physiologically based oral absorption modeling and simulation in drug development are highlighted and suggestions for maximizing its impact are provided.

Discovery and in Vivo Evaluation of the Potent and Selective PI3Kδ Inhibitors 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-0687) and 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-5-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-1430).

Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either 6a or 7 resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development.

Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM-8508 and AM-9635 as Potent and Selective PI3Kδ Inhibitors.

Lead optimization efforts resulted in the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 1 (AM-8508) and 2 (AM-9635), with good pharmacokinetic properties. The compounds inhibit B cell receptor (BCR)-mediated AKT phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based assays. These compounds which share a benzimidazole bicycle are effective when administered in vivo at unbound concentrations consistent with their in vitro cell potency as a consequence of improved unbound drug concentration with lower unbound clearance. Furthermore, the compounds demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in rats, where the blockade of PI3Kδ activity by inhibitors 1 and 2 led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH.

Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kδ inhibitors for inflammation and autoimmune disease.

The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.

Improved pharmacokinetics of AMG 517 through co-crystallization part 2: analysis of 12 carboxylic acid co-crystals.

Intrinsic dissolution, powder dissolution, and the pharmacokinetics (PK) of 12 carboxylic acid co-crystals of AMG 517 were determined and compared. Dissolution studies were performed in fasted simulated intestinal fluid (FaSIF). A control dissolution experiment was conducted with the free base in FaSIF plus sorbic acid to compare with the AMG 517 sorbic acid co-crystal (SRA). Suspension formulations in 1% polyvinylpyrrolidone K25 in water were administered orally at 100 mg/kg to rats. All co-crystals were found to have faster intrinsic and powder dissolution rates in FaSIF as well as higher area under the concentration-time curves (AUC) in rat PK investigations compared with the free base. The control dissolution experiment indicates that the increase in dissolution rate of SRA over the free base is not due to the presence of sorbic acid in the dissolution medium. Linear correlation of dissolution rate and AUC among the 12 co-crystals was moderate, indicating that in vitro dissolution is a valuable method to predict whether a co-crystal will improve the exposure of a poorly soluble pharmaceutical ingredient; however, in vivo testing may be required to determine the extent.

Synthesis and optimization of novel 4,4-disubstituted cyclohexylbenzamide derivatives as potent 11ß-HSD1 inhibitors.

The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11ß-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models.

Improved pharmacokinetics of AMG 517 through co-crystallization. Part 1: comparison of two acids with corresponding amide co-crystals.

The dissolution and pharmacokinetics (PK) of two carboxylic acid co-crystals (cinnamic acid and benzoic acid) with the corresponding amide co-crystals (cinnamamide and benzamide) of AMG 517 were investigated. Powder and intrinsic dissolution studies were performed in fasted simulated intestinal fluid (FaSIF). Suspension formulations in 1% polyvinylpyrrolidone K25 in water were administered orally at 100 mg/kg to rats. The four co-crystals were found to have faster intrinsic and powder dissolution rates in FaSIF than the free base. This correlated with a 2.4- to 7.1-fold increase in the area under the concentration-time curve in rat PK investigations. When contrasting the acid to its corresponding amide co-crystal, cinnamamide shows improvement over cinnamic acid, while benzamide and benzoic acid perform similarly.

Characterization of amorphous API:Polymer mixtures using X-ray powder diffraction.

Recognizing limitations with the standard method of determining whether an amorphous API-polymer mixture is miscible based on the number of glass transition temperatures (T(g)) using differential scanning calorimetry (DSC) measurements, we have developed an X-ray powder diffraction (XRPD) method coupled with computation of pair distribution functions (PDF), to more fully assess miscibility in such systems. The mixtures chosen were: dextran-poly(vinylpyrrolidone) (PVP) and trehalose-dextran, both prepared by lyophilization; and indomethacin-PVP, prepared by evaporation from organic solvent. Immiscibility is detected when the PDF profiles of each individual component taken in proportion to their compositions in the mixture agree with the PDF of the mixture, indicating phase separation into independent amorphous phases. A lack of agreement of the PDF profiles indicates that the mixture with a unique PDF is miscible. In agreement with DSC measurements that detected two independent T(g) values for the dextran-PVP mixture, the PDF profiles of the mixture matched very well indicating a phase separated system. From the PDF analysis, indomethacin-PVP was shown to be completely miscible in agreement with the single T(g) value measured for the mixture. In the case of the trehalose-dextran mixture, where only one T(g) value was detected, however, PDF analysis clearly revealed phase separation. Since DSC can not detect two T(g) values when phase separation produces amorphous domains with sizes less than approximately 30 nm, it is concluded that the trehalose-dextran system is a phase separated mixture with a structure equivalent to a solid nanosuspension having nanosize domains. Such systems would be expected to have properties intermediate to those observed for miscible and macroscopically phase separated amorphous dispersions. However, since phase separation has occurred, the solid nanosuspensions would be expected to exhibit a greater tendency for physical instability under a given stress, that is, crystallization, than would a miscible system.

Assessment of defects and amorphous structure produced in raffinose pentahydrate upon dehydration.

The progressive conversion of crystalline raffinose pentahydrate to its amorphous form by dehydration at 60 degrees C, well below its melting temperature, was monitored by X-ray powder diffraction over a period of 72 h. The presence of defects within the crystal structure and any amorphous structure created was determined computationally by a total diffraction method where both coherent long-range crystalline order and incoherent short-range disorder components were modeled as a single system. The data were analyzed using Rietveld, pair distribution function (PDF), and Debye total diffraction methods. Throughout the dehydration process, when crystalline material was observed, the average long-range crystal structure remained isostructural with the original pentahydrate material. Although the space group symmetry remained unchanged by dehydration, the c-axis of the crystal unit cell exhibited an abrupt discontinuity after approximately 2 h of drying (loss of one to two water molecules). Analysis of diffuse X-ray scattering revealed an initial rapid build up of defects during the first 0.5 h with no evidence of any amorphous material. From 1-2 h of drying out to 8 h where the crystalline structure is last observed, the diffuse scattering has both amorphous and defect contributions. After 24 h of drying, there was no evidence of any crystalline material remaining. It is concluded that the removal of the first two waters from raffinose pentahydrate created defects, likely in the form of vacancies, that provided the thermodynamic driving force and disorder for subsequent conversion to the completely amorphous state.