Pure Active Pharmaceutical Ingredients Research Articles

Development of a Practical and Greener Process for the Dual Leucine Zipper Kinase Inhibitor GDC-0134 Comprising Two SNAr Reactions, Oxidation and Suzuki Coupling

A sustainable second-generation process for GDC-0134 was developed with a particular focus on safety and greenness, while complying with strong specifications to supply pivotal clinical studies. Through these efforts, we discovered solvents to replace the solvents classified as substances of very high concern by the REACH regulation in two SNAr steps. We further established a safer and faster way to oxidize the sulfanyl to the sulfonyl intermediate by dosing H2O2 at higher temperatures, reducing accumulation while minimizing uncontrolled H2O2 decomposition. The reaction conditions for the Suzuki coupling and the second SNAr were modified to increase the selectivity in these two steps. A change in the solvent for the final crystallization allowed operation at higher concentrations and delivery of a highly pure active pharmaceutical ingredient (API). The new improved process reduced the process mass intensity by approximately 40% and was successfully used to produce 150 kg of GDC-0134.

Solid-State Study of the Structure, Dynamics, and Thermal Processes of Safinamide Mesylate─A New Generation Drug for the Treatment of Neurodegenerative Diseases.

Safinamide mesylate (SM), the pure active pharmaceutical ingredient (API) recently used in Parkinson disease treatment, recrystallized employing water–ethanol mixture of solvents (vol/vol 1:9) gives a different crystallographic form compared to SM in Xadago tablets. Pure SM crystallizes as a hemihydrate in the monoclinic system with the P21 space group. Its crystal and molecular structure were determined by means of cryo X-ray crystallography at 100 K. SM in the Xadago tablet exists in anhydrous form in the orthorhombic crystallographic system with the P212121 space group. The water migration and thermal processes in the crystal lattice were monitored by solid-state NMR spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. SM in Xadago in the high-humidity environment undergoes phase transformation to the P21 form which can be easily reversed just by heating up to 80 °C. For the commercial form of the API, there is also a reversible thermal transformation observed between Z′ = 1 ↔ Z′ = 3 crystallographic forms in the 0–20 °C temperature range. Analysis of molecular motion in the crystal lattice proves that the observed conformational polymorphism is forced by intramolecular dynamics. All above-mentioned processes were analyzed and described employing the NMR crystallography approach with the support of advanced theoretical calculations.

Structure and Glass Transition Temperature of Amorphous Dispersions of Model Pharmaceuticals with Nucleobases from Molecular Dynamics.

Glass transition temperature (Tg) is an important material property, which predetermines the kinetic stability of amorphous solids. In the context of active pharmaceutical ingredients (API), there is motivation to maximize their Tg by forming amorphous mixtures with other chemicals, labeled excipients. Molecular dynamics simulations are a natural computational tool to investigate the relationships between structure, dynamics, and cohesion of amorphous materials with an all-atom resolution. This work presents a computational study, addressing primarily the predictions of the glass transition temperatures of four selected API (carbamazepine, racemic ibuprofen, indomethacin, and naproxen) with two nucleobases (adenine and cytosine). Since the classical non-polarizable simulations fail to reach the quantitative accuracy of the predicted Tg, analyses of internal dynamics, hydrogen bonding, and cohesive forces in bulk phases of pure API and their mixtures with the nucleobases are performed to interpret the predicted trends. This manuscript reveals the method for a systematic search of beneficial pairs of API and excipients (with maximum Tg when mixed). Monitoring of transport and cohesive properties of API–excipients systems via molecular simulation will enable the design of such API formulations more efficiently in the future.

Therapeutic deep eutectic solvent based on osthole and paeonol: Preparation, characterization, and permeation behavior

Recently, a new type of drug delivery system termed therapeutic deep eutectic solvent (THEDES) was developed to increase the solubility and/or permeation ability of drugs, where an active pharmaceutical ingredient (API) was included as the component in the eutectic system. In this work, we designed a new THEDES based on two well-known active pharmaceutical ingredients (APIs), osthole and paeonol. The macroscopic properties and the microscopic structures were investigated by various techniques. The THEDES has been proven to retain the bioactivities of pure APIs and shows better solubility than pure APIs in water. Furthermore, an O/W microemulsion formulation was constructed with THEDES as the oil phase and TX-100 and 1,2-propanediol serving as the surfactant and the co-surfactant respectively, which showed good stability and an average size of 50 nm. The permeation behavior of the THEDES was compared to that of pure APIs in gel form, and the results suggested that the THEDES had a better permeation ability than pure APIs at the same concentrations. Hence, a multifunctional drug delivery system with great simplicity and convenience was demonstrated herein, showing great potential application in the transdermal delivery systems.

Fluconazole-tartaric acid co-crystal formation and its mechanical properties


 Introduction: The formation of co-crystal is widely studied to obtain more favourable physicochemical properties than the pure active pharmaceutical ingredient (API). The co-crystal formation between an anti-fungal drug, fluconazole (FLU), and tartaric acid (TAR) has been investigated and its impact on mechanical properties has also been studied. 
 Methods: The co-crystal of FLU-TAR (1:1) molar ratio was prepared by ultrasound-assisted solution co-crystallization (USSC) method with ethanol as the solvent. Polarization microscopy was used to observe the crystal morphology. Meanwhile, powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) methods were used to characterise the co-crystal formation. The mechanical properties of the co-crystal, such as flowability and tablet-ability, were compared with pure FLU. 
 Results: Photomicroscopes revealed the unique crystal morphology of the USSC product was different from the two starting components. The typical PXRD pattern was shown by the USSC product, which indicated the formation of FLU-TAR co-crystal. In addition, the DSC thermogram revealed 169.2°C as the melting point of the FLU-TAR co-crystal, which is between the melting points of FLU and TAR. It indicates that FLU-TAR co-crystal has better flowability and tablet-ability than pure FLU. 
 Conclusion: FLU-TAR co-crystal is one of the alternative solid forms for a raw material in pharmaceutical tablet preparation because it has better mechanical properties than pure fluconazole.

Characterization of Pharmaceutical Tablets Using UV Hyperspectral Imaging as a Rapid In-Line Analysis Tool.

A laboratory prototype for hyperspectral imaging in ultra-violet (UV) region from 225 to 400 nm was developed and used to rapidly characterize active pharmaceutical ingredients (API) in tablets. The APIs are ibuprofen (IBU), acetylsalicylic acid (ASA) and paracetamol (PAR). Two sample sets were used for a comparison purpose. Sample set one comprises tablets of 100% API and sample set two consists of commercially available painkiller tablets. Reference measurements were performed on the pure APIs in liquid solutions (transmission) and in solid phase (reflection) using a commercial UV spectrometer. The spectroscopic part of the prototype is based on a pushbroom imager that contains a spectrograph and charge-coupled device (CCD) camera. The tablets were scanned on a conveyor belt that is positioned inside a tunnel made of polytetrafluoroethylene (PTFE) in order to increase the homogeneity of illumination at the sample position. Principal component analysis (PCA) was used to differentiate the hyperspectral data of the drug samples. The first two PCs are sufficient to completely separate all samples. The rugged design of the prototype opens new possibilities for further development of this technique towards real large-scale application.

Overview: Enzyme-catalyzed Enantioselective Biotransformation of Chiral Active Compounds Used in Hypertension Treatment

Enzymatic kinetic resolution is one of the methods which allows for the synthesis of enantiomerically pure various active pharmaceutical ingredients. In contrast to chemical routes, enzymatic reactions have characteristics, including mild reaction conditions, a few byproducts, and relatively high activity of the used enzymes. β-adrenolytic drugs are widely used in the treatment of hypertension and cardiovascular disorders. Due to the fact that β- blockers possess an asymmetric carbon atom in their structure, they are presented in two enantiomeric forms. It was reported by many studies that only the (S)-enantiomers of these drugs possess the desired therapeutic effect, whereas the administration of the racemate may cause dangerous side effects, such as bronchoconstriction or diabetes. Nevertheless, β- blockers are still commercially available drugs mainly used in medicine as racemates, whereas there are several methods that are widely used in order to obtain enantiomerically pure compounds.

Comparison between twin-screw and high-shear granulation - The effect of filler and active pharmaceutical ingredient on the granule and tablet properties

The aim of the study was to compare continuous twin-screw granulation (TSG) with batch-wise high-shear granulation (HSG). Two different formulations containing either microcrystalline cellulose (MCC) and mannitol or MCC and dibasic calcium phosphate (DCP) as fillers were used. Three different active pharmaceutical ingredients (APIs) (allopurinol, paracetamol and metformin HCl) were used as model substances. To find the suitable liquid-to-solid (L/S) ratio for the granulations, preliminary trials were carried out using a mixer torque rheometry (MTR). Both granule and tablet properties were studied. Granules were characterized with respect to particle size distribution and flowability, while tablets were analysed for tensile strength. Both granulation techniques produced granules with unimodal particle size distribution after milling with the selected L/S ratios. Continuous TSG was less sensitive for liquid amount than HSG when comparing the granule size and tensile strength of tablets. The tabletability of the MCC-DCP formulation was decreased after the wet granulation, whereas the tabletability of MCC-mannitol was increased after wet granulation. Tablets made of TSG granules had a higher tensile strength than HSG tablets for all formulations. Even the APIs with poor compaction properties produced tablets with sufficient tensile strength. All the model substances behaved in a same way independently of the particle size and solubility of the pure API. These findings confirmed that continuous twin-screw granulation is a good alternative to batch-wise high-shear granulation.

Modification of the Microtox® Basic Solid Phase Test: A new application for the ecotoxicological studies on poorly soluble antihypertensive drugs

Increasing consumption of angiotensin II receptor blockers (ARBs: valsartan, losartan potassium, telmisartan) is inevitably associated with their appearance in the environment and impact on aquatic and terrestrial organisms. Since the pharmaceuticals do not occur as pure substances in the environment, but as complex mixtures with other active pharmaceutical ingredients (APIs) and excipients used in pharmaceutical formulations, we compared the ecotoxicity of ARBs in various forms: as pure APIs, in pharmaceutical formulations and in mixtures with hydrochlorothiazide (HCT). Because the studied APIs are poorly water-soluble, the Microtox® Basic Solid Phase Test, utilizing bacteria Aliivibrio fischeri, has been modified by using a neutral matrix. Thus, this test, which is correlated with other tests for higher aquatic organisms, may be applied for the ecotoxicological evaluation of poorly soluble APIs. This is the first study reflecting the real situation in the environment, where non-target species are exposed to the pharmaceuticals, which can be dissolved/suspended in the liquid medium or adsorbed on the solid matrix. The results obtained indicate that the excipients are not inert substances and their presence in the environment may cause an increased risk to non-target organisms. Moreover, antagonistic effects were observed for two-component drug-drug (ARBs−HCT) mixtures.

Improving Feedability of Highly Adhesive Active Pharmaceutical Ingredients by Silication

Loss-in-weight feeders play a vital role in assuring blend and content uniformity as well as lot-to-lot powder traceability in continuous manufacturing. Irregular flow from the feeders propagates through the system, potentially resulting in out-of-specification product. Powder properties such as density, cohesion, and adhesion can cause large variability in the flow rate of ingredients from powder feeders. Feeding of active pharmaceutical ingredients (API) can be difficult because of inherently poor flow, low density, high cohesion, and adhesion. API was chosen due to known adhesion behavior inside feeders during continuous operations. The selected APIs were blended with nanosized silica, in a V-blender, to provide separation between the API particles and reducing the effect of interparticle forces. The material was characterized by standard pharmaceutical techniques to identify bulk changes between the as-received and the blended API. The coated API was then fed using a Coperion K-Tron KT-20 pharmaceutical loss-in-weight feeder. The material was dispensed onto a catch scale, recording mass versus time, and analyzed for relative standard deviation and deviation from the set point. Additionally, the mass of the remaining API in the feeder after the run ended was compared between the API and silica-blended API. Blending APIs with nanosized silica successfully improved API feeding performance despite their intrinsic highly adhesive and cohesive behavior. Both the pure and silica-blended APIs were fed using a twin screw powder feeder. When feeding unsilicated APIs, large variability in flow rate and screw speed were observed, and large amounts of material coated the inside of the hopper and screws. When the adhesive APIs were blended with nanosized silica and fed through a loss-in-weight feeder, there was significantly less adhesion to the feeder, and the material was dispensed with significant reduction in flow rate and screw speed variability. This work provides a means to increase the applicability of continuous manufacturing by enabling the practitioner to manage adverse impact of cohesive material properties on feeder performance. Blending highly adhesive API with silica reduces the adhesion of the API to the feeder hopper and screws, while also improving the deviation in mass flow rate exiting the feeder.

Selective detection of active pharmaceutical ingredients in tablet formulations using solid-state NMR spectroscopy

Atomic-level characterization of active pharmaceutical ingredients (API) is crucial in pharmaceutical industry because APIs play an important role in physicochemical properties of drug formulations. However, the analysis of targeted APIs in intact tablet formulations is less straightforward due to the coexistence of excipients as major components and different APIs at dilute concentrations (often below 10 ​wt% loading). Although solid-state (ss) NMR spectroscopy is widely used to investigate short-range order, polymorphism, and pseudo-polymorphism in neat pharmaceutical compounds, the analysis of complex drug formulations is often limited by overlapped signals that originate from structurally different APIs and excipients. In particular, such examples are frequently encountered in the analysis of 1H ssNMR spectra of pharmaceutical formulations. While the high-resolution in 1H ssNMR spectra can be attained by, for example, high magnetic fields accompanied by fast magic-angle spinning (MAS) approaches, the spectral complexity associated with the mixtures of compounds hinders the accurate determination of chemical shifts and through-space proximities. Here we propose a fast MAS (70 ​kHz) NMR experiment for the selective detection of 1H signals associated with an API from a severely overlapped NMR spectrum of a tablet formulation. Spectral simplification is achieved by combining (i) symmetry-based dipolar recoupling (SR412) rotational-echo saturation-pulse double-resonance (RESPDOR) with phase-modulate (PM) saturation pulses, (ii) radio frequency-driven recoupling (RFDR), and (iii) double-quantum excitation using Back-to-Back (BaBa) pulse sequence elements. First, 1H sites in close proximities to 14N nuclei of an API are excited using a PM-S-RESPDOR sequence, and simultaneously, the other unwanted 1H signals of excipients are suppressed. Then, 1H magnetization transfer to adjacent 1H sites in the API is achieved by spin diffusion process using a RFDR sequence, which polarizes to 1H sites within the crystalline API regions of the drug formulation. Next, a PM-S-RESPDOR-RFDR sequence is combined with a Back-to-Back (BaBa) sequence to elucidate local-structures and 1H–1H proximities of the API in a dosage form. The PM-S-RESPDOR-RFDR-BaBa experiment is employed in one- (1D) and two-dimensional (2D) versions to selectively detect the 1H ssNMR spectrum of l-cysteine (10.6 ​wt% or 0.11 ​mg) in a commercial formulation, and compared with the spectra of neat l-cysteine recorded using a standard BaBa experiment. The 2D 1H double-quantum−single-quantum (DQ-SQ) spectrum of the API (l-cysteine)-detected pharmaceutical tablet is in good agreement with the 2D 1H DQ-SQ spectrum obtained from the pure API molecule. Furthermore, the sensitivity and robustness of the experiment is examined by selectively detecting 1H{14N} signals in an amino acid salt, l-histidine.H2O.HCl.

Solid State Stability and Kinetics of Degradation for Candesartan-Pure Compound and Pharmaceutical Formulation.

The aim of this work was to assess the impact of an excipient in a pharmaceutical formulation containing candesartan cilexetil over the decomposition of the active pharmaceutical ingredient and to comparatively investigate the kinetics of degradation during thermolysis in an oxidative atmosphere under controlled thermal stress. To achieve this, the samples were chosen as follows: pure candesartan cilexetil and a commercial tablet of 32 mg strength. As a first investigational tool, Universal attenuated total reflection Fourier transform infrared (UATR-FTIR) spectroscopy was chosen in order to confirm the purity and identity of the samples, as well as to check if any interactions took place in the tablet between candesartan cilexetil and excipients under ambient conditions. Later on, samples were investigated by thermal analysis, and the elucidation of the decomposition mechanism was achieved solely after performing an in-depth kinetic study, namely the use of the modified non-parametric kinetics (NPK) method, since other kinetic methods (American Society for Testing and Materials—ASTM E698, Friedman and Flynn–Wall–Ozawa) led to inadvertencies. The NPK method suggested that candesartan cilexetil and the tablet were degraded by the contribution of two steps, the main being represented by chemical degradation and the secondary being a physical transformation. The excipients chosen in the formulation seemed to have a stabilizing effect on the decomposition of the candesartan cilexetil that was incorporated into the tablet, relative to pure active pharmaceutical ingredient (API), since the apparent activation energy for the decomposition of the tablet was 192.5 kJ/mol, in comparison to 154.5 kJ/mol for the pure API.

Emtricitabine, Tenofovir, and Rilpivirine from their degradation products Analysis by HPLC

A simple, expeditious, and explicit stability-indicating High-Performance Liquid Chromatography (HPLC) analytical test method was developed for the quantitative analysis of Emtricitabine, Tenofovir, and Rilpivirine in bulk drugs and combined dosage formulations. Using the ICH guidelines method was validated using a C18 column of size 250 mm X 4.6 mm, 5µ, maintained at 25oC. The total run time maintained was 10 min. Acetonitrile and 0.1% TEA prepared in water adjusted with pH 3.0 was adapted as a mobile phase. The injection volume of samples was 20μL and UV-DAD detector system set at 265 nm used for UV detection. As per the ICH guidelines method was validated. The retention times were observed as 2.52, 3.27, 6.70 min for Emtricitabine, Rilpivirine, and Tenofovir disoproxyl fumarate, respectively. Linearity ranges were observed 24-56 µg/mL Emtricitabine, 3-7 µg/mL Rilpivirine and 30-70 µg/mL Tenofovir. Relative Standard Deviation not exceed 2%. In contract to the conventional method of HPLC, a method developed was able to give better resolution of swift retention times in the separation of various degradation products along with the pure active pharmaceutical ingredients. The proposed method exhibited excellent reproducibility and repeatability. The stress studies performed by following ICH guidelines indicated that the present HPLC method is explicit and stability-indicating. Since the present HPLC method has the capacity to separate the drugs with high resolution in tablet dosage forms, hence the method can be exploited for routine analysis of quality control sample and stability analysis.

What if Cocrystallization Fails for Neutral Molecules? Screening Offered Eutectics as Alternate Pharmaceutical Materials: Leflunomide-a Case Study

Background: The manuscript is aimed to optimize the biopharmaceutical parameters of a poorly soluble, neutral anti-rheumatic drug ‘leflunomide’ by preparing its non-covalent derivatives (NCDs). For this various monocarboxylic acids- (adipic acid, picolinic acid) and dicarboxylic acids (maleic acid, malonic acid, sorbic acid), as well as pyridine carboxamide derivatives (nicotinamide, isonicotinamide), are used as coformers. Methods: The novel solid forms were rationally prepared and systematically characterized. Further, these solid forms were subjected to equilibrium solubility and intrinsic dissolution rate (IDR) analysis in three aqueous media (pH 1.2, pH 4.5 and pH 6.8). In vivo plasma studies in male Wistar rats were done to assess the effect on area under the curve (AUC) and the maximum concentration (Cmax) of leflunomide in prepared solid forms. Results: These NCD were primarily characterized to be eutectics rather than cocrystals as expected. The stoichiometry was established by phase diagrams. The negative value of heat of mixing indicated them to be of cluster type. In addition, leflunomide in eutectics showed approximately 9 folds increase in solubility up to 4 hours. Besides this, approximately 4 folds enhancement in the in IDR was also observed. Maximum increase in bioavailability indicated by enhanced values of AUC and Cmax (490.29 μg h-1 mL-1 and 31.42 μg mL-1, respectively) for leflunomide-maleic acid eutectic in comparison to pure LEF (AUC: 193.20 μg h-1 mL-1 and Cmax: 12.09 μg mL-1). Conclusion: The unsuccessful cocrystallization experiments were found be the latent eutectics. The evaluation of these novel eutectics of poorly soluble drug exhibited possibility to further amplify the scope of accessible material phase options other than pure active pharmaceutical ingredient (API) without disturbing the structural integrity.

Mixed-Suspension, Mixed-Product Removal Studies of Ciprofloxacin from Pure and Crude Active Pharmaceutical Ingredients: The Role of Impurities on Solubility and Kinetics

Despite the known effects of foreign species on crystallization and the frequently large number of impurities present in multistep pharmaceutical syntheses, the early characterization of continuous crystallization operations may be limited by the availability of representative crude material. As part of the development of an end-to-end process for ciprofloxacin HCl monohydrate, this work evaluates the impact of upstream impurities on mixed-suspension, mixed-product removal (MSMPR) crystallization kinetics. The kinetic parameters for nucleation and crystal growth in MSMPR crystallization have been estimated for the commercial, purified active pharmaceutical ingredient (API), as well as crude API containing approximately 60 unknown impurities. Results show that, while the upstream impurities did not have a significant impact on the nucleation rate, both the temperature-dependent growth rate coefficient and the growth activation energy decreased in crude API crystallization. This behavior implies that the ef...

Chemometric study of the excipients’ influence on polymorphic-behavior. Mefenamic acid as case of study

The assessment of polymorphism is a problematical issue for regulatory agencies, because variations among crystalline forms of active pharmaceutical ingredient (API) can lead to changes in the efficacy and safety of formulated product. Such conversions are very hard to be detected, thus, the development of techniques for the identification, characterization and quantification of polymorphs results essential in all stages of the manufacturing process.The presence of excipients in formulated products may change the crystal stability of an API, by catalyzing a polymorphic transformation or stabilizing the less stable form. As paradox, all suitable analytical techniques (spectroscopies, thermal analysis, NMR and DRX, and others) for polymorphic analysis are affected by excipients. A deep understanding of the polymorphism-excipient relationship is in full accordance with Quality by Design (QbD) paradigm, the systematic approach focused in quality building into a product based in the full understanding of the products and process.In this work, a novel approach based on thermal stress, MIR monitoring, multivariate curve resolution with alternating least squares (MCR-ALS) and kinetic analysis was developed and applied to monitor polymorphism behavior of model API in formulated products.Commercial tablets, physical mixtures and commercial API, were processed and analyzed under the proposed approach. Commercial tablets of MFA revealed a fast conversion to Form II, contrasting to the behavior of the pure API. Physical mixtures showed similar behavior to commercial tablets, thus reduction in transformation times was related to MFA-excipients physical interaction, even at surface level. Calorimetric studies support the conclusion obtained.The developed approach could be extended to others APIs and other stress sources (humidity, solvents, mechanical forces and its combinations), being a valuable tool for QbD environment.

Melt-based screening method with improved predictability regarding polymer selection for amorphous solid dispersions

The predictability of preformulation screening tools for polymer selection in amorphous solid dispersions (ASD) regarding supersaturation and precipitation was systematically examined. The API-polymer combinations were scaled up by means of hot-melt extrusion and spray-drying to verify the predictions. As there were discrepancies between a solvent-based screening and performance of ASD, a new screening tool with improved predictability at minimal investments of time and material is presented. The method refinement resulted in a better correlation between the screening and ASD prototypes.So far, a purely solvent-based screening was used which consisted of film casting by rapid solvent evaporation. This approach was improved by applying a heating step after film casting. Four representative polymers were tested with two different model active pharmaceutical ingredients (API) under non-sink dissolution conditions. Polyvinylpyrrolidone (PVP) based polymers showed no benefit towards pure API in the solvent-based screening but good supersaturation as ASD formulations. The extrudates with the cellulose derivatives hydroxypropylmethylcellulose acetate succinate (HPMCAS) and cellulose acetate phthalate (CAP) showed lower supersaturation than predicted by the solvent-based screening but performed especially well as spray-dried dispersions (SDD).False negative results for PVP-co-vinyl acetate (PVP-VA64) could be avoided by using the new melt-based screening. Furthermore, comparing the results from the two different screening methods allowed predicting the performance of extrudates vs. SDD with cellulose derivatives as polymeric excipients.

Co-Amorphous Simvastatin-Nifedipine with Enhanced Solubility for Possible Use in Combination Therapy of Hypertension and Hypercholesterolemia.

The high index of simultaneous incidence of hypertension and hypercholesterolemia in the population of many countries demands the preparation of more efficient drugs. Therefore, there is a significant area of opportunity to provide as many alternatives as possible to treat these illnesses. Taking advantage of the solubility enhancement that can be achieved when an active pharmaceutical ingredient (API) is obtained and stabilized in its amorphous state, in the present work, new drug-drug co-amorphous formulations (Simvastatin SIM- Nifedipine NIF) with enhanced solubility and stability were prepared and characterized. Results show that the co-amorphous system (molar ratio 1:1) is more soluble than the pure commercial APIs studied separately. Aqueous dissolution profiles showed increments of solubility of 3.7 and 1.7 times for SIM and NIF, correspondingly, in the co-amorphous system. The new co-amorphous formulations, monitored in time, (molar fractions 0.3, 0.5 and 0.7 of SIM) remained stable in the amorphous state for more than one year when stored at room temperature and did not show any signs of crystallization when re-heating. Inspection on the remainder of a sample after six hours of dissolution showed no recrystallization, confirming the stability of co-amorphous system. The enhanced solubility of the co-amorphous formulations makes them promising for simultaneously targeting of hypertension and hypercholesterolemia through combination therapy.

Salts of Amoxapine with Improved Solubility for Enhanced Pharmaceutical Applicability

The objective of pharmaceutical cocrystallization is to create crystalline analogues that have vastly different properties, such as solubility, melting point, stability, and bioavailability from that observed in the pure active pharmaceutical ingredients (APIs). Amoxapine is a benzoxazepine derivative and exhibits antidepressant properties. Amoxapine has very low solubility in water, so it was cocrystallized with natural acids in a 1:1 ratio in appropriate solvents by the solvent-drop grinding method. Single crystals of cocrystals were grown by the solvent evaporation method in water, ethanol, and methanol. Crystal structures of API salts were determined by single-crystal X-ray diffraction. Salts were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction. Solubility of salts was determined in water by the shake-flask method at 37 °C using UV–vis spectroscopy. Salts of amoxapine with different acids were successfully developed, and their crystal structure was determined. Enhanced solubility was found in the salts of amoxapine for pharmaceutical application in drug formulation.

DNP-enhanced solid-state NMR spectroscopy of active pharmaceutical ingredients.

Solid-state NMR spectroscopyhas become a valuable tool for the characterization of both pure and formulated active pharmaceutical ingredients (APIs). However, NMR generally suffers from poor sensitivity that often restricts NMR experiments to nuclei with favorable properties, concentrated samples, and acquisition of one-dimensional (1D) NMR spectra. Here, we review how dynamic nuclear polarization (DNP) can be applied to routinely enhance the sensitivity of solid-state NMR experiments by one to two orders of magnitude for both pure and formulated APIs. Sample preparation protocols for relayed DNP experiments and experiments on directly doped APIs are detailed. Numerical spin diffusion models illustrate the dependence of relayed DNP enhancements on the relaxation properties and particle size of the solids and can be used for particle size determination when the other factors are known. We then describe the advanced solid-state NMR experiments that have been enabled by DNP and how they provide unique insight into the molecular and macroscopic structure of APIs. For example, with large sensitivity gains provided by DNP, natural isotopic abundance, 13 C-13 C double-quantumsingle-quantum homonuclear correlation NMR spectra of pure APIs can be routinely acquired. DNP also enables solid-state NMR experiments with unreceptive quadrupolar nuclei such as 2 H, 14 N, and 35 Cl that are commonly found in APIs. Applications of DNP-enhanced solid-state NMR spectroscopyfor the molecular level characterization of low API load formulations such as commercial tablets and amorphous solid dispersions are described. Future perspectives for DNP-enhanced solid-state NMR experiments on APIs are briefly discussed.