Pharmaceutical Solid Forms Research Articles

Thermal Compatibility of New ACEI Derivatives with Popular Excipients Used to Produce Solid Pharmaceutical Formulations.

Background/Objectives: Increasing drugs' stability and adequately protecting them against degradation will ensure a decrease in their price and broader availability of pharmaceutical substances. This is of great importance, especially for drugs used to treat the most common diseases in the population, such as hypertension. The study examined two newly synthesized substances from the angiotensin I-converting enzyme inhibitor (ACEI) group as potential drugs. ACEIs are among the leading drugs used in the treatment of hypertension in the world. The chemical modifications of the tested substances applied concerned the places most susceptible to degradation. The presented work analyzed the compatibility of new derivatives with selected excipients used in pharmacy. Methods: Thermogravimetric (TGA) and differential thermal analyses (c-DTA) were used as the main methods. In addition, non-thermal methods such as colorimetry analysis, Fourier-transform infrared (FTIR) and UV spectroscopy were used. Results: Based on the conducted studies, it can be concluded that the incompatibility of IND-1 with glucose anhydrous and lactose monohydrate occurs only when the mixture is stored at higher temperatures. For the remaining IND-1 and IND-2 mixtures with excipients, compatibility was demonstrated. Conclusions: The obtained results confirmed the usefulness of the applied thermal analyses (TGA and c-DTA) for assessing the compatibility of the tested potential drugs with excipients. However, in the case of incompatibility reactions of substances occurring under the influence of elevated temperatures, such as the Maillard reaction, it is necessary to use non-thermal methods to obtain the right result.

Characterization of extracted alpha cellulose from Manihot esculenta (cassava) peels as formulation aid for paracetamol tablet

Background: Alpha-cellulose as a pharmaceutical excipient can be employed as a binding agent in tablet formulation. Cassava peels husk are waste agricultural material and is being investigated for its α-cellulose for use in oral solid pharmaceutical formulation. Purpose: The objective of this study is to extract α-cellulose from cassava peels agro-industrial waste using a standard method, subject the extracted cassava peels cellulose and determine its phytochemical and physicochemical properties of formulated granules of paracetamol. Methods: Alpha-cellulose from cassava peel was extracted using alkali method. The fresh peels were prepared, milled into slurry and de-watered to obtain a coarse wet material, dried, milled and sieved to obtain very fine powdered particles. Phytochemical analysis and characterization of extracted α-cellulose powder were determined. Differential scanning calorimetry (DSC), scanning electron micrographs (SEM), and x-ray diffractogram (XRD) analysis of extracted cassava peel cellulose were done. Paracetamol granules was prepared by wet granulation using varying concentrations of the binders. Results: DSC and XRD results revealed a semi-crystalline material with amorphous and crystalline regions. while the SEM showed a lumpy structure and reticular shape. Pre-compression evaluations of the formulated batches of paracetamol granules showed that cassava peels cellulose (CPC) have similar flow properties with those of microcrystalline cellulose BP (MCC) and acacia BP (ACA) powders respectively. The granules have free flow properties with average angles of repose (CPC ≤ 27.60 MCC < 26.90 and ACA ≤ 25.60), compressibility index (CPC ≤ 25, MCC ≤ 23 and ACA ≤ 21.7%), Hausner’s ratio (CPC ≤ 1.32, MCC ≤ 1.31, and ACA ≤ 1.27) respectively. Conclusion: The extracted cassava peel α-cellulose was found ideal as pharmaceutical excipient binder in oral solid dosage forms.

Thermal stability, preformulation, and kinetic degradation studies for gestrinone

AbstractGestrinone is an active pharmaceutical ingredient used in the treatment of endometriosis as capsules, with ongoing evaluation for intravaginal administration, while also having been studied for its potential antitumoral effects. The purpose of this study was to determine the compatibility of gestrinone with four excipients used in the development of solid pharmaceutical formulations (α-lactose monohydrate, magnesium stearate, starch, and talc) and to obtain a fully characterized thermoanalytical profile of gestrinone with the help of kinetic analysis. Preformulation studies were carried out on 1:1 mass/mass binary mixtures between gestrinone and each excipient by instrumental screening under ambient conditions using ATR-FTIR spectroscopy investigations, and later by studying the effect of thermal treatment over the samples (TG/DTG/DSC). The obtained results suggest that under ambient conditions, no chemical interactions take place between the active pharmaceutical ingredient and selected excipients, whereas under thermal stress incompatibilities are observed in all systems. The mechanism of decomposition was preliminary evaluated by the ASTM E698 and later completed by the isoconversional methods of Friedman, Kissinger–Akahira–Sunose, and Flynn–Wall–Ozawa, which suggest similar mean activation energies. The mechanism of decomposition was elucidated in the last part of the study, by employing the modified NPK method. This method suggests that gestrinone is thermally degraded by the contribution of two individual processes, both consisting of superimposed physical transformations and chemical degradations.

Forensic application of sandpaper spray ionization mass spectrometry (SPS-MS): Direct analysis of solid pharmaceutical formulations and edible cannabis products.

In this work, we employed a new ambient ionization mass spectrometry technique, sandpaper spray mass spectrometry (SPS-MS), as an efficient tool to analyze pills and tablets of pharmaceutical formulations. The following samples were analyzed: regulators of blood pressure, cholesterol, and diabetes, and drugs for the treatment of erectile dysfunction (ED). Additionally, a hard candy of Cannabis sativa containing Δ9-tetrahydrocannabinol (Δ9-THC) and its related isomer cannabidiol (CBD) was also evaluated. The surfaces of the samples, without any prior treatment, were sanded onto triangular-cut sandpaper, and full MS scans (and MS/MS) were acquired in both positive and negative ionization modes. SPS-MS (and MS/MS) allowed for prompt detection of the active pharmaceutical ingredients (APIs) in each formulation. Other components of the formulations, added as excipients, were also tentatively identified. The results described herein indicate that the SPS-MS technique can be applied to fast screening of pills and tablets being potentially used as an efficient tool to detect counterfeit pharmaceutical and illicit products, a current issue of increasing concern.

Salt hydrates as a source to form co-amorphous systems when prepared in the absence of water: Hydrogen bond analysis

Pharmaceutical multi-component solid forms, including salts, co-crystals and co-amorphous systems (COAMs), are used to modify the physicochemical and pharmaco-kinetic properties of these drugs. Gefitinib and two co-formers, bumetanide and furosemide, form salt hydrates in the presence of water and COAMs in the absence of water using solvent evaporation method. Molecular dynamic simulation and isolated water analysis reveal that water molecules play a multi-faceted role in stabilizing the crystalline salt hydrate systems by reducing the total energy of the system, establishing hydrogen bonds, and maintaining the crystalline 3D structures. Salt hydrates are also formed in the presence of water using liquid-assisted grinding. In the absence of water, intermolecular interactions between Gefitinib and co-formers facilitate the formation of COAMs during ball milling and quench cooling, i.e., in the absence of water. These findings provide valuable insights to the formation of salt hydrates and COAMs by controlling the presence of water.

The Effect of Formulation Variables on the Manufacturability of Clopidogrel Tablets via Fluidized Hot-Melt Granulation-From the Lab Scale to the Pilot Scale.

Solid pharmaceutical formulations with class II active pharmaceutical ingredients (APIs) face dissolution challenges due to limited solubility, affecting in vivo behavior. Robust computational tools, via data mining, offer valuable insights into product performance, complementing traditional methods and aiding in scale-up decisions. This study utilizes the design of experiments (DoE) to understand fluidized hot-melt granulation manufacturing technology. Exploratory data analysis (MVDA) highlights similarities and differences in tablet manufacturability and dissolution profiles at both the lab and pilot scales. The study sought to gain insights into the application of multivariate data analysis by identifying variations among batches produced at different manufacturing scales for this technology. DoE and MVDA findings show that the granulation temperature, time, and Macrogol type significantly impact product performance. These factors, by influencing particle size distribution, become key predictors of product quality attributes such as resistance to crushing, disintegration time, and early-stage API dissolution in the profile. Software-aided data mining, with its multivariate and versatile nature, complements the empirical approach, which is reliant on trial and error during product scale-up.

In Vitro and In Vivo Evaluation of Magnetic Floating Dosage Form by Alternating Current Biosusceptometry.

Floating controlled systems seek to extend the gastric retention time (GRT) of solid pharmaceutical forms by sustaining buoyancy in the stomach without affecting gastric emptying rates. This investigation aimed to evaluate a magnetic floating drug delivery system (MFDDS) under diverse physiological conditions (pressure and viscosity) using an Alternating Current Biosusceptometry (ACB) system by conducting assessments in vitro and in vivo. For in vitro experiments, MFDDSs were placed under different pressures (760, 910, and 1060 mmHg) and viscosities (1, 50, 120, and 320 mPa·s) for evaluation of floating lag time (FLT). For in vivo experiments, eight healthy volunteers participated in two phases (fasting and fed) for gastric parameters (GRT, FLT, and OCTT-orocaecal transit time) assessment, employing the ACB system. The results indicated that pressure, viscosity, and FLT were directly proportional in the in vitro assay; in addition, increases in the OCTT (fasting = 241.9 ± 18.7; fed = 300 ± 46.4), GRT (fasting = 139.4 ± 25.3; fed = 190.2 ± 47.7), and FLT (fasting = 73.1 ± 16.9; fed = 107.5 ± 29.8) were detected in vivo. Our study emphasizes that the ACB system is a valuable technique, and it is capable of tracking and imaging MFDDS in in vitro and in vivo experiments.

Rapid polymorphic screening using sessile microdroplets: competitive nucleation of mannitol polymorphs

Using microdroplets, we developed an approach to rapidly measure the nucleation statistics of polymorphs. It can be useful in the routine screening of pharmaceutical solid forms, and in the study of the competitive nature of polymorphic nucleation.

Compatibility Assessment of Novel Orodispersible Film Vehicle for Personalized Medicine with Selected Active Pharmaceutical Ingredients.

Orodispersible films (ODFs) are solid pharmaceutical forms for rapid local or systemic release of active ingredients. They are formed by a water-soluble polymer film that hydrates rapidly, adhering and dissolving immediately when placed on the tongue or in the oral cavity. In this paper, we describe the compatibility and disintegration times of compounded ODFs using OrPhylloTM, a new ready-to-use-vehicle, and APIs from different pharmacological classes, such as 5-hydroxytryptophan (5-HTP) 50 mg, bromopride 5 mg, coenzyme Q10 20 mg, melatonin 3 mg, resveratrol 5 mg, tadalafil 10 mg, vitamin B12 1 mg, or vitamin D3 2000 UI. ODFs were compounded and, subsequently, the samples were assayed using HPLC at initial (t = 0), 7 days (t = 7), 14 days (t = 14), 30 days (t = 30), 60 days (t = 60), 90 days (t = 90), 120 days (t = 120), 150 days (t = 150), and 180 days (t = 180) after compounding. Given the percentage of recovery of the APIs within the films, the beyond-use date of the final products (API + vehicle) was at least 90 days for vitamin D3, 150 days for bromopride and 5-HTP, and 180 days for coenzyme Q10, tadalafil, vitamin B12, resveratrol, and melatonin, when stored at room temperature. The average disintegration time was 46.22 s. This suggests that the OrPhylloTM vehicle is suitable for compounding ODFs with APIs from different pharmacological classes, with good compatibility and fast disintegration.

Development of a formulation of potassium iodide tablets as an antidote against nuclear incidents

ObjectivesPotassium iodide (KI) is a treatment to neutralize radioactive agents that could be inhaled or ingested in nuclear incidents. The inorganic salt KI constitutes a source of iodine, which in the body acts by accumulating in the thyroid gland, producing its saturation, and thus preventing the fixation of radioactive iodine species. In Spain, the Military Defence Pharmacy Centre (CEMILFARDEF) was challenged to develop this antidote to be distributed among the population surrounding nuclear power plants, in only one new solid pharmaceutical form for oral administration, in order to replace the two pharmaceutical forms available, which are capsules for adults and oral solution for children, considered less versatile. MethodsA selection of excipients was carried out to achieve pharmacotechnical behaviour suitable for the industrial manufacture of potassium iodide in tablets, complying with the pre-established process and finished product quality parameters. The development allowed the preparation of three industrial-sized batches on which the stability of the developed formulation was studied. ResultsAn uncoated 65 mg double-scored potassium iodide tablet was developed using easily accessible excipients in the formulation and direct compression as the manufacturing method. The formula complied with the stability tests, with which the development carried out can respond to the eventual demand that its elaboration would entail in the event of nuclear incidents. ConclusionsThe developed formulation of a 65 mg double-scored potassium iodide tablet allows the great variability of user needs, from infants to adults with a single pharmaceutical form, which additionally implies logistical benefits in distribution, stock control and appropriate renewal according expiration dates, among the population surrounding nuclear power plants and available to deployed military personnel, in the event of potential nuclear incidents.

Highly Efficient Production of Desired Solid Forms of Drugs with Improved Mechanical Properties via an Organic Solvent-Free Sublimation Process

The pharmaceutical industry is required to constantly broaden its development areas and accelerate technical transformation because of the continued global rise in medicine consumption. However, the usage of organic solvents in pharmaceutical production results in up to 20 million tons annually of chemical waste, causing a serious environmental problem. Here, we proposed a solvent-free sustainable chemical technology, sublimation crystallization, for highly efficient screening and preparation of pharmaceutical solid forms (i.e., polymorphs), which eliminates the wastes associated with solvent use from the source. By adjusting the parameters of sublimation crystallization, we have obtained multiple polymorphs of several important drugs, including the antituberculosis drug pyrazinamide (PZA) and nonsteroidal anti-inflammatory drugs (NSAIDs), flufenamic acid (FFA) and mefenamic acid, particularly γ form of PZA and polymorphs IV and VII of FFA, which are difficult to produce from conventional solution crystallization methods. Mechanical property measurements from both powder and single crystal tests reveal that the γ form of PZA readily prepared by sublimation crystallization has the most excellent tabletability properties. In situ crystal growth observations indicate a direct vapor-to-crystal growth mechanism for the sublimation crystallization process consistent with conventional vapor phase deposition. Furthermore, the governing factors and growth mechanisms of sublimation and solution crystallization processes were analyzed and discussed, and it was found that the rate-limiting step of crystal growth is the surface-integration process in solution crystallization, whereas it becomes the surface diffusion process in sublimation crystallization. Overall, our developed sublimation crystallization provides a promising green technology for the development and production of (new) drugs, broadening the thinking behind the development of sustainable chemicals.

Potent Lipophilic Melatoninergic x-fluoro-y-methoxy Substituted Phenylalkylamides: Molecular Dynamics Calculations and in vitro Modified Release in Aqueous Media from Tablet Formulations.

We report herein on the design and development of matrix tablets containing potent synthetic melatonin (MLT) receptor analogues, the x-fluoro-y-methoxy substitiuted phenylalkylamides (compounds I-IV), the preparation and melatoninergic potency of which was recently communicated. > Methods: The presence of the fluorine atom in compounds I-IV, besides not affecting their binding affinity, compared to the pineal hormone melatonin, it also slows down their metabolism, which is a major drawback of MLT. However, as fluorine increases the lipophilicity, solid pharmaceutical formulations of I-IV, involving the appropriate biopolymers for their modified release in aqueous media, were developed in the context of the present work. > Results: The release profile of analogues I-IV was found to be similar to that of MLT and also of the commercially available drug, Circadin®. Some of these systems are suitable for dealing with sleep onset problems, whilst others for dealing with combined sleep onset/sleep maintenance problems. > Conclusion: Apart from the nature and relevant content of the formulants used, this bimodal release profile of the new analogues depends, to a large extent, on the diverse structural arrangement of their side chains in space, as nicely demonstrated by the molecular dynamics calculations, conducted in the context of this study. >.

Decoding Supramolecular Packing Patterns from Computed Anisotropic Deformability Maps of Molecular Crystals.

The ability to encode and embed desired mechanical properties into active pharmaceutical ingredient solid forms would significantly advance drug development. In recent years, computational methods, particularly dispersion-corrected density functional theory (DFT), have come of age, opening the possibility of reliably predicting and rationally engineering the mechanical response of molecular crystals. Here, many-body dispersion and Tkatchenko-Scheffler dispersion-corrected DFT were used to calculate the elastic constants of a series of archetypal systems, including paracetamol and aspirin polymorphs and model hydrogen-bonded urea and π-π-bound benzene crystals, establishing their structure-mechanics relations. Both methods showed semiquantitative and excellent qualitative agreement with experiment. The calculations revealed that the plane of maximal Young's modulus generally coincides with extended H-bond or π-π networks, showing how programmable supramolecular packing dictates the mechanical behavior. In a pharmaceutical setting, these structure-mechanics relations can steer the molecular design of solid forms with improved physicochemical and compression properties.

Vapor Sorption and Halogen-Bond-Induced Solid-Form Rearrangement of a Porous Pharmaceutical.

A porous, nonsolvated polymorph of the voltage-gated sodium channel blocker mexiletine hydrochloride absorbs iodine vapor to give a pharmaceutical cocrystal incorporating an I2Cl- anion that forms a halogen-π interaction with the mexiletine cations. The most thermodynamically stable form of the compound does not absorb iodine. This example shows that vapor sorption is a potentially useful and underused tool for bringing about changes in pharmaceutical solid form as part of a solid form screening protocol.

Pharmaceutical novel solid forms of Milrinone with advanced physicochemical properties

Milrinone (MLN) is a second-generation bipyridine phosphodiesterase (PDE) inhibitor developed by modifying amrinone chemically. It is a PDE-III antagonist that promotes cardiac function and systemic vasodilator in chronic decongested cardiovascular disease by increasing cAMP levels. It is classified under Biopharmaceutics Classification System (BCS) class II, which implies, high permeability and low water solubility. Using mechanochemical and solution crystallization, five novel molecular solids of the cardioprotective drug (MLN) with Generally Recognized As Safe (GRAS) co-formers, namely 2-hydroxybenzoic acid (2-HBA), 2,3-dihydroxybenzoic acid (2,3-DHBA), 2,4-dihydroxybenzoic acid (2,4-DHBA), fumaric acid (FA), and adipic acid (AA) were successfully synthesized. All the solid forms were characterized by PXRD, SCXRD, and thermal analysis (TGA and DSC). The structural analysis of the complexes reveals that the dimeric interaction of MLN itself remains intact in all the structures. Molecular assemblies made with AA and 2,3-DHBA produced channel structures, whereas the remaining formed various forms of sheet structures. A physicochemical property analysis revealed that the synthesized molecular solid exhibits higher solubility than the parent form. Furthermore, the theoretical analyses corroborate well with the solubility of molecular complexes. We believe that the novel solid forms for MLN are promising candidates for addressing poor solubility difficulties while also providing a new avenue for further improving the material's physicochemical properties.

Use of Liquid Pharmaceutical Forms and Correct Handling of Solid Forms in the Dysphagic Patient

Introduction: The presence of dysphagia is a rather common event, both physiologically in elderly people and the presence of neurological, maxillofacial, or upper digestive pathologies. Many drugs are routinely taken in solid form for the convenience of use, however, in such patients, it becomes difficult to swallow tablets or capsules and it is important to both have liquid alternatives and possibly handle the solid forms correctly. In this article, we want to describe the correct handling of solid pharmaceutical forms or the transition to liquid ones where present.
 Methodology: the article was written by integrating one's knowledge of pharmacology and pharmaceutical techniques with printed material and online articles extracted from databases google scholar and PubMed.
 Discussion and Conclusions: The liquid forms, where they exist, are important in the management of drug therapy in the dysphagia patient. In the absence of therapeutic alternatives or liquid forms of the same principle, the solid forms can be manipulated within certain limits, paying attention to the interactions with nutritional mixtures and other drugs and above all not obstructing the probe and not compromising the kinetic and dynamic characteristics of the active ingredient.

Preparation of solid pharmaceutical forms of celecoxib with immediate-release and sustained-release by using wet granulation techniques and evaluation of their in vitro characteristics

Preparation of solid pharmaceutical forms of celecoxib with immediate-release and sustained-release by using wet granulation techniques and evaluation of their in vitro characteristics

Mechanochemistry - A Promising Tool on the Synthesis of Organometallic Pincer Compounds: Current State and Future Perspectives

Abstract: Among the different synthethic proceedures available where the reactivity of substances is exploited using solid–state chemistry, such as microwave irradiation, ultrasound (sonochemistry), photochemistry, and mechanochemistry, the latter stands out as a synthetic tool on various areas of chemistry and materials sciences, acquiring great relevance in recent years. Thus, mechanochemistry has been applied in different areas such as organic synthesis, preparation of metal complexes, multicomponent pharmaceutical solid forms, catalysis, polymers, etc. However, despite the attractiveness of this sustainable technique, its application in the synthesis of coordination and organometallic compounds has been very incipient. On the other hand, pincer compounds have been a privileged ligand platform that has been profusely used for the synthesis of organometallic and coordination compounds for the last 20 years, finding applications on a large number of areas of chemistry, this being particularly true in the case of catalysis, being able to activate bonds difficult to activate such as C-H bonds, due in part to their characteristic thermal robustness. In this sense, on this perspective paper we present the current state of mechanochemistry in the preparation of organometallic pincer compounds and discuss future perspectives for the synthesis of these foremost interesting species via mechanochemistry.

Avaliação de prescrições pediátricas de hidroxiureia para pacientes com doença falciforme

Hydroxyurea (HU) was one of the main advances in the treatment of sickle cell disease. The use of the drug in children in Brazil is still off-label and is only available in solid pharmaceutical form. The objective of the present study is to evaluate the strategies for adapting the solid dosage form for use in children with sickle cell disease. This is a descriptive study, with the analysis of pediatric HU prescriptions and the application of questionnaires to those responsible in the period from January to March 2018. 43 prescriptions were analyzed, and two forms of adaptation were identified, 1) conventional dilution: dilution of the drug in a pre-prescribed quantity - determined amount of water, followed by administration of part of the solution obtained (22) (51%), and 2) use of the holiday or intermittent dose recommendation (21) (49%). All patients using the conventional dilution strategy discarded the remainder of the drug from the domestic sewage system. In addition, incorrect administration of the drug was identified in one patient. The lack of an appropriate pharmaceutical form for the pediatric population can lead to risks of incorrect administration and unnecessary expenses with drug disposal, in addition to improper disposal that compromises environmental factors. This study reinforces the need to develop pharmaceutical forms that are more suitable for children.

Evaluation of pediatric hydroxyurea prescriptions for patients with sickle cell disease

Hydroxyurea (HU) was one of the main advances in the treatment of sickle cell disease. The use of the drug in children in Brazil is still off-label and is only available in solid pharmaceutical form. The objective of the present study is to evaluate the strategies for adapting the solid dosage form for use in children with sickle cell disease. This is a descriptive study, with the analysis of pediatric HU prescriptions and the application of questionnaires to those responsible in the period from January to March 2018. 43 prescriptions were analyzed, and two forms of adaptation were identified, 1) conventional dilution: dilution of the drug in a pre-prescribed quantity - determined amount of water, followed by administration of part of the solution obtained (22) (51%), and 2) use of the holiday or intermittent dose recommendation (21) (49%). All patients using the conventional dilution strategy discarded the remainder of the drug from the domestic sewage system. In addition, incorrect administration of the drug was identified in one patient. The lack of an appropriate pharmaceutical form for the pediatric population can lead to risks of incorrect administration and unnecessary expenses with drug disposal, in addition to improper disposal that compromises environmental factors. This study reinforces the need to develop pharmaceutical forms that are more suitable for children.