Coformer-Dependent Physical Stability in a Series of Naringenin-Based Coamorphous Materials with Caffeine, Theophylline, and Theobromine.

PURPOSE: To investigate the production and physical stability of coamorphous materials (CAM) of naringenin (NAR) and coformers-caffeine, theophylline or theobromine (CAF/THY/THE, respectively). We independently assessed the impact of moisture and temperature on the physical stability of CAMs, and transformation products after destabilization were examined. METHODS: Neat grinding, liquid assisted grinding and water slurry were selected to prepare multi-component materials with NAR and CAF, THY or THE. The physical stability of CAMs was investigated at 65°C/<10%RH, 21°C/85% RH and 21°C/<10% RH. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were employed to monitor for recrystallization during the stability studies. Glass forming ability of amorphous NAR was assessed to understand CAM formation and physical stability. RESULTS: NAR:THY and NAR:THE CAMs showed physical stability for approximately nine months, under 21°C/<10% RH while NAR:CAF CAMs destabilized in 2.5 weeks. All CAMs recrystallized within a week at 65°C/<10%RH, and the physical stability at 21°C/85% RH was in the order of - NAR:THY > NAR:THE > NAR:CAF. NAR:THY produced 1:1 cocrystal under all storage conditions, while NAR:CAF destabilized to a 1:1 cocrystal at high RH but a physical mixture at high temperature. NAR:THE was found to recrystallize as a physical mixture in all conditions. NAR was found to be strong glass, with moderate kinetic fragility and good glass forming ability. CONCLUSION: Five naringenin-based multi-component solids were generated in this study: 3 new CAMs, 1 new cocrystal, and 1 previously reported cocrystal. Destabilization of CAMs was found to be exposure specific and coformer dependent.

Current clinical trials and patent update on lung cancer: a retrospective review.

Several clinical trials using different interventions are currently being sponsored to combat lung cancer at its different stages. The purpose of this study was to provide a portfolio of those trials. All active, open and recruiting clinical trials registered at ClinicalTrials.gov up to March 2018 were included. Information related to 6092 registered lung cancer trials was downloaded. Phase II trials were in the majority, comprising nearly 48.7% of total clinical trials with industry the major sponsor (41.3%) followed by NIH (12.3%). Multicenter studies were the norm accounting for 47.9% and the main study location was the USA (50.9%). Common interventions were radiation (26%), surgery (22%) and EGFR inhibitors (17%). Patent information includes major patent filing office and sponsors. The data analysis provides a comprehensive description of lung cancer trials.

Structure-mechanics and improved tableting performance of the drug-drug cocrystal metformin:salicylic acid.

Drug-drug cocrystals (DDC) represent a unique subset of pharmaceutical materials offering distinct advantages in combination therapies, pharmacokinetics, and patient compliance. However, their structure-function relationships are rarely reported despite its central importance in successful medicine. A material-sparing approach consisting of a molecular and structural perspective is reported to evaluate tabletability of a model DDC, metformin:salicylic acid, relative to its components: metformin HCl (MET) and sodium salicylate (SAL). MET alone displayed a very poor tabletability, which could be attributed to its isotropic and stiff interaction topology. SAL displayed a highly anisotropic interaction topology with layers of strongly hydrogen-bonded salicylate molecules promoting deformation and tabletability. This is also confirmed by its low moduli. DDC yielded intermediate stiffness and elastic anisotropy material with an improved plastic flow and overall better tabletability. Overall, DDC is a promising therapeutic class requiring the physical-mechanical evaluation to assure their processability to enjoy their therapeutic advantages.

Ultrasound-mediated topical delivery of econazole nitrate with potential for treating Raynaud's phenomenon.

The study aims to assess the ultrasound-assisted econazole nitrate (EN) permeation from topically applied formulations with potential for treating Raynaud's phenomenon. Optimization of ultrasound parameters such as the distance of the horn, application time and amplitude were performed. In vitro percutaneous absorption studies were performed using econazole formulations (F2_HPMC dispersion, F4_Lipoderm® Activemax™ Cream) across the ultrasound-treated porcine skin and were compared with the control group (skin samples without ultrasound). Histology and ATR-FTIR studies were performed on treated skin samples. A constant frequency (20 kHz) ultrasound application with 40% amplitude, 0.5 cm distance between ultrasound horn and the skin surface for 2 min was optimized. The permeation of EN was found to be higher from ultrasound-treated skin samples than the control group. Drug permeation from F2_HPMC dispersion was found to be higher as compared to the other formulations and the marketed EN cream. Histological evaluation confirmed that F2_HPMC dispersion showed no signs of toxicity. ATR-FTIR studies revealed a slight increase in the CH2 stretching vibrations (~2920 cm-1 and 2850 cm-1) in ultrasound-treated skin samples as compared with the control. In conclusion, the ultrasound-assisted transdermal delivery of F2_HPMC dispersion could be further studied as a new therapy for Raynaud's phenomenon.

Molecular Interpretation of the Compaction Performance and Mechanical Properties of Caffeine Cocrystals: A Polymorphic Study.

The 1:1 caffeine (CAF) and 3-nitrobenzoic acid (NBA) cocrystal (CAF:NBA) displays polymorphism. Each polymorph shares the same docking synthon that connects individual CAF and NBA molecules within the asymmetric unit; however, the extended intermolecular interactions are significantly different between the two polymorphic modifications. These alternative interaction topologies translate to distinct structural motifs, mechanical properties, and compaction performance. To assist our molecular interpretation of the structure-mechanics-performance relationships for these cocrystal polymorphs, we combine powder Brillouin light scattering (p-BLS) to determine the mechanical properties with energy frameworks calculations to identify potentially available slip systems that may facilitate plastic deformation. The previously reported Form 1 for CAF:NBA adopts a 2D-layered crystal structure with a conventional 3.4 Å layer-to-layer separation distance. For Form 2, a columnar structure of 1D-tapes is displayed with CAF:NBA dimers running parallel to the (110) crystallographic direction. Consistent with the layered crystal structure, the shear modulus for Form 1 is significantly reduced relative to Form 2, and moreover, our p-BLS spectra for Form 1 clearly display the presence of low-velocity shear modes, which support the expectation of a low-energy slip system available for facile plastic deformation. Our energy frameworks calculations confirm that Form 1 displays a favorable slip system for plastic deformation. Combining our experimental and computational data indicates that the structural organization in Form 1 of CAF:NBA improves the compressibility and plasticity of the material, and from our tabletability studies, each of these contributions confers superior tableting performance to that of Form 1. Overall, mechanical and energy framework data permit a clear interpretation of the functional performance of polymorphic solids. This could serve as a robust screening approach for early pharmaceutical solid form selection and development.

Understanding the Tabletability Differences between Indomethacin Polymorphs Using Powder Brillouin Light Scattering.

PURPOSE: The unconventional tabletability of the indomethacin polymorphs - α and γ - are investigated from a topological and mechanical perspective using powder Brillouin light scattering (p-BLS) to identify the specific structure-performance relationship in these materials. METHOD: Indomethacin (γ-form) was purchased and used to prepare the α polymorph. Powder X-ray diffraction was used to confirm phase identity, while p-BLS was used to obtain the mechanical properties. Energy frameworks were determined with Crystal Explorer to visualize the interaction topologies. Using a Carver press and a stress-strain analyzer, the tableting performance of each polymorph was determined. RESULTS: Polymorph-specific acoustic frequency distributions were observed with distinct, zero-porosity, aggregate elastic moduli determined. The p-BLS spectra for α-indomethacin display a population of low-velocity shear modes, indicating a direction of facilitated shear. This improves slip-mediated plasticity and tabletability. Our p-BLS spectra experimentally indicates that a low-energy slip system is available to α-indomethacin which supports ours and previous energy framework calculations. Despite a 2d-layered crystal motif favorable for shear deformation, the γ-form displays a higher shear modulus that is supported by our hydrogen-bonding analysis of γ-indomethacin. CONCLUSION: Our experimental, mechanical data is consistent with the predicted interaction topologies and these two inputs combined permit a comprehensive, molecular understanding of polymorph-specific tabletability.

Evaluation of topical econazole nitrate formulations with potential for treating Raynaud's phenomenon.

The purpose of this work was to design and characterize a topical formulation of econazole nitrate (EN) with potential for treating Raynaud's phenomenon (RP). Four topical dosage forms (F1_topical solution, F2_HPMC or hydroxypropyl methylcellulose dispersion, F3_VersaBase® cream, and F4_Lipoderm® Activemax™ Cream) containing 3% w/w EN were prepared and characterized for drug content, pH, viscosity, spreadability, drug crystallinity, stability, and in vitro permeation using Franz cells across pig ear skin, and results were compared to the 1% marketed EN cream. All four formulations had acceptable physical and visual characteristics required for topical application, with 3% w/w EN. The order of amount of drug permeated from highest to lowest was F2 (10.27%) > F4 (2.47%) > F1 (2.28%) > F3 (1.47%) > marketed formulation (0.22%). Formulation F2 showed better penetration of the drug into the stratum corneum, epidermis, and dermis layers. The drug concentration in the stratum corneum and epidermis was approximately 10-20 times higher with F2 compared to the marketed formulation. All formulations were found to be stable for up to 6 months. All four EN formulations were found to be better than the 1% marketed cream. Formulation F2_HPMC dispersion could be further explored as a treatment option for RP.

Brillouin Light Scattering: Development of a Near Century-Old Technique for Characterizing the Mechanical Properties of Materials.

Brillouin light scattering (BLS), a technique theoretically described nearly a century back by the French physicist Léon Brillouin in 1922, is a light-scattering method for determining the mechanical properties of materials. This inelastic scattering method is described by the Bragg diffraction of light from a propagating fluctuation in the local dielectric. These fluctuations arise spontaneously from thermally populated sound waves intrinsic to all materials, and thus BLS may be broadly applied to transparent samples of any phase. This review begins with a brief historical overview of the development of BLS, from its theoretical prediction to the current state of the art, and notes specific technological advancements that enabled the development of BLS. Despite the broad utility of BLS, no commercial spectrometer is currently available for purchase, but rather individual components are assembled to suit a specific application. Central to any BLS spectrometer is the interferometer, and its performance characteristics-scanning or non-scanning, multi-passing, and stabilization-are critical considerations for spectrometer design. Consistent with any light-scattering method, the frequency shift is a key observable in BLS, and we summarize the connection of this measurement to evaluate the mechanical properties of materials. With emphasis toward pharmaceutical materials analysis, we introduce the traditional BLS approach for single-crystal elasticity, and this is followed by a discussion of more recent developments in powder BLS. We conclude our review with a perspective on future developments in BLS that may enable BLS as a novel addition to the current catalog of process analytical technologies.

Curcumin in combination with anti-cancer drugs: A nanomedicine review.

A huge surge of research is being conducted on combination therapy with anticancer compounds formulated in the form of nanoparticles (NPs). Numerous advantages like dose minimalization and synergism, reversal of multi drug resistance (MDRs), enhanced efficacy have emerged with nanoencapsulation of chemotherapeutic agents with chemo-sensitizing agent like curcumin. Within last couple of years various nano-sized formulations have been designed and tested both in vitro with cell lines for different types of cancers and in vivo with cancer types and drug resistance models. Despite the combinatorial models being advanced, translation to human trials has not been as smooth as one would have hoped, with as few as twenty ongoing clinical trials with curcumin combination, with less than 1/10th being nano-particulate formulations. Mass production of nano-formulation based on their physico-chemical and pharmacokinetics deficits poses as major hurdle up the ladder. Combination of these nano-sized dosage with poorly bioavailable drugs, unspecific target binding ability and naturally unstable curcumin further complicates the formulation aspects. Emphasis is now therefore being laid on altering natural forms of curcumin and usage of formulations like prodrug or coating of curcumin to overcome stability issues and focus more on enhancing the pharmaceutical and therapeutic ability of the nano-composites. Current studies and futuristic outlook in this direction are discussed in the review, which can serve as the basis for upcoming research which could boost commercial translational of improved nano-sized curcumin combination chemotherapy.

Aggregate Elasticity and Tabletability of Molecular Solids: a Validation and Application of Powder Brillouin Light Scattering.

Describing the elastic deformation of single-crystal molecular solids under stress requires a comprehensive determination of the fourth-rank stiffness tensor (Cijkl). Single crystals are, however, rarely utilized in industrial applications, and thus averaging techniques (e.g., the Voigt or Reuss approach) are employed to reduce the Cijkl (or its inverse Sijkl) to polycrystalline aggregate mechanical moduli. With increasing elastic anisotropy, the Voigt and Reuss-averaged aggregate moduli can diverge dramatically and, provided that drug molecules almost exclusively crystallize into low-symmetry space groups, warrants a significant need for accurate aggregate mechanical moduli. This elasticity data, which currently is largely absent for pharmaceutical materials, is expected to aid understanding how materials respond to direct compression and tablet formation. Powder Brillouin light scattering (p-BLS) has recently demonstrated facile access to porosity-independent, aggregate mechanical moduli. In this study, we extend our previous p-BLS model for obtaining mechanical properties and validate our approach against a broad library of molecular solids with diverse intermolecular interaction topologies and with previously determined Cijkl which permits benchmarking our results. Our Young's and shear moduli determined with p-BLS strongly correlate, with limited bias (i.e., a near 1:1 relation), with the Voigt-averaged Young's and shear moduli determined using the Cijkl. Through follow-on tabletability studies, we introduce initial classifications of tabletability behavior based on the results of our p-BLS studies and the apparent elastic anisotropy. With further development, this approach represents a robust and novel method to potentially identify materials for optimum tabletability at early developmental stages.

Organogels in Drug Delivery: A Special Emphasis on Pluronic Lecithin Organogels.

Organogels have emerged as an alternative carrier for small and macromolecules via transdermal, oral, rectal and ophthalmic routes. Pluronic lecithin organogels (PLO gels) are lecithin-based organogels widely used in compounding pharmacies as a vehicle for enhancing the transdermal permeability of many therapeutic drugs. However, the scientific and systematic evidence in support of how well PLO gels help in transdermal delivery is scanty. Recently, some clinical studies have reported nearly complete lack of bioavailability of certain topically administered drugs from PLO gels. The present review aims at summarizing gels and organogels, with a focus on the use of PLO gels in transdermal drug delivery. A special emphasis is placed on controversies looming over the use of PLO gels as a delivery platform for drugs via transdermal route. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.