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Indonesia's vast archipelago offers abundant seawater resources, holding the potential for salt production. Salt, a vital commodity in human life, typically contains sodium chloride and impurities like Ca2+, Mg2+, SO42−, and K+. Pharmaceutical salt is an industrial category adhering to pharmacopoeial standards regarding sodium chloride levels and impurity content, ensuring quality for drug preparations in Indonesia. Prior research indicates that recrystallisation, specifically evaporation crystallisation, enhances salt quality by increasing NaCl content. Chemical precipitating agents like NaOH and Na2CO3 can be introduced to improve salt purity further. This study aims to identify optimal conditions for pharmaceutical salt production from processed salt raw materials, considering crystallisation time, stirring speed, chemical additives (NaOH and Na2CO3), and double crystallisation stages. The method commences with pre-treatment, involving salt dissolution in distilled water to saturation, with the addition of precipitating agents as per designated variables. Precipitates formed from precipitating agents (NaOH and Na2CO3) are isolated through filtration. The filtrate undergoes evaporation crystallisation at 103 °C, varying between single and double crystallisation. Salt crystals are separated, dried, and weighed to calculate yield. Pharmaceutical salt is analysed for water content, NaCl, and impurities (Ca2+, Mg2+, SO42−, and K+). The optimal conditions for pharmaceutical salt production were double crystallisation with a 20 % excess of chemicals (NaOH and Na2CO3), 100 min of crystallisation time, and a stirring speed of 600 rpm. This yielded a 15 % NaCl content of 99.87 %, Mg2+ at 0 ppm, Ca2+ at 69.6 ppm, SO42− at 366 ppm, K+ at 370 ppm, and water content at 0.166 %. Notably, the pharmaceutical salt production process generates no waste, as byproducts like Mg(OH)2 and CaCO3 can be recycled and hold commercial value. However, it is essential to re-evaluate raw materials and technologies to address the market's high cost and competitiveness issues.

• Pharmaceutical salt of isoniazid (INH) with orotic acid (OA) was obtained. • INH−OA exhibits sustained-release performance. • INH−OA demonstrates enhanced tabletability. Isoniazid (INH) is a first-line antitubercular drug characterized by its high solubility and rapid absorption following oral administration, which poses challenges in maintaining sustained therapeutic concentrations. To address this issue, we have developed a novel pharmaceutical salt of INH with orotic acid (OA). Single-crystal X-ray diffraction (XRD) analysis revealed that intermolecular proton transfer occurs between the carboxyl group of OA and the pyridine nitrogen site of INH, resulting in a salt comprising INHH+ cations and OA− anions. Solubility and dissolution studies indicated that INH−OA exhibits significantly reduced solubility and decelerated intrinsic dissolution rate (IDR). Specifically, solubility reductions were observed to be 74.24% in pH 1.2 HCl solution and 90.29% in pH 6.8 phosphate buffer solution. The IDR of the salt was found to be 2.62% and 0.96% of that of pure INH in pH 1.2 and pH 6.8 aqueous media, respectively. Additionally, INH−OA demonstrated improved tabletability. These findings suggest that the formation of this salt significantly enhances the pharmaceutical properties of INH. [Display omitted] [ABSTRACT FROM AUTHOR]

The aim of this work is to improve the solubility and bioavailability of chlortetracycline and the function of the immune response. Chlortetracycline bisulfate and chlortetracycline mesylate were successfully synthesized and characterized with several techniques, including spectroscopy, chromatography and mass spectrometry, which demonstrated that the C4-dimethylamino group of chlortetracycline can accept a proton from sulfuric acid and methanesulfonic acid to form the corresponding salts. In addition, chlortetracycline bisulfate and chlortetracycline mesylate were more soluble in water than chlortetracycline hydrochloride, but the antibacterial activity was not enhanced. The influences of chlortetracycline hydrochloride, chlortetracycline bisulfate and chlortetracycline mesylate on chlortetracycline and immunoglobulin concentrations in mouse serum were also investigated. These results suggested that the chlortetracycline bisulfate and chlortetracycline mesylate have good bioavailability and strong immune response and have potential applications in animal breeding and formulation technologies.

With the aim to improve the hygroscopic stability of palmatine chloride (PMTCl), an unreported single crystal of PMT–SSA (C21H20NO4·C7H5O6S·H2O) is prepared by the solvent evaporation method and characterized. A comprehensive analysis of the structure and Hirshfeld surface reveals that π–π stacking plays a crucial role in accumulating PMT–SSA. As expected, the hygroscopic stability of PMT–SSA is significantly improved compared with that of PMTCl. This may be due to the presence of π–π stacking in the structure of PMT–SSA which improves the hygroscopic stability. The present work inaugurates an avenue for improving the hygroscopic stability of active pharmaceutical ingredients and provides a novel crystalline product with a bright commercial prospect. Unfortunately, the maximum solubility of PMT–SSA is lower than that of PMTCl. How to improve its solubility will be explored in subsequent studies. However, it is surprising that PMT–SSA shows advantages with regard to antibacterial properties in comparison to PMTCl. [ABSTRACT FROM AUTHOR]

• Two new pharmaceutical salts of enrofloxacin with aromatic acids were prepared. • The two hydrated salts have the same crystal packing patterns. • Hydrogen bonding interactions in two salts were analyzed by theoretical calculations. • The hydrated salt with two hydroxyl groups in the coformer is more stable. In the present work, the effect of the number of hydroxyl groups in the hydroxybenzoic acid on the cocrystallization of enrofloxacin, including the conformation of enrofloxacin in the crystals, packing and physicochemical properties, has been investigated in an attempt to explore the possible general relationship between the number of coformers hydroxyl groups and the changes in the properties of the active pharmaceutical molecule. With this purpose, two new enrofloxacin pharmaceutical salt crystals, enrofloxacin 3-hydroxybenzoic acid hydrate (ENR-3HBA-HYD) and enrofloxacin 3, 5 dihydroxybenzoic acid hydrate (ENR-3, 5HBA-HYD) have been synthesised and their crystal structures have been determined by infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction, and single-crystal X-ray diffraction. The conformational differences between the enrofloxacin molecules in the two hydrated salts were found to be very small and both have the same packing mode. Interestingly, the presence of one water molecule in the ENR-3HBA-HYD lattice stabilizes chain formation. Whereas the ENR-3, 5HBA-HYD lattice contains two water molecules that act as bridges between chains to build a 2D layered structure. The hydrogen bonding interactions of the two salts were further investigated with frontier molecular orbitals and molecular surface electrostatic potential. Additionally, Solubility and hygroscopicity experiments showed that ENR-3HBA-HYD has higher solubility and, conversely, ENR-3, 5HBA-HYD is more advantageous in anti-hygroscopicity. These differences in properties can be well explained by thermal analysis, Hirshfeld surface and energy framework analysis. [Display omitted] [ABSTRACT FROM AUTHOR]

Salts of active pharmaceutical ingredients are prepared in order to improve the solubility and bioavailability of the parent drug. In this study, we present the synthesis and characterization of ibuprofen isobutanolammonium salt. Analysis of the synthesized salt was carried out by thermal methods such as differential scanning calorimetry (DSC), thermogravimetry as well as other methods like Fourier transform infrared spectroscopy and powder X-ray diffraction. The DSC curves of the parent drug ibuprofen and its isobutanolammonium salt were found to be different, indicating that a chemical reaction had taken place between the drug and the salt former (2-amino-2-methyl-propan-1-ol). Powder X-ray study analysis also indicated that the product obtained from the reaction was a salt and not a co-crystal of ibuprofen. Solubility analysis of the salt was also performed and clearly showed that salt formation of ibuprofen improved its solubility. [ABSTRACT FROM AUTHOR]

A multicomponent pharmaceutical salt formed by the isoquinoline alkaloid berberine (5,6‐dihydro‐9,10‐dimethoxybenzo[g]‐1,3‐benzodioxolo[5,6‐a]quinolizinium, BBR) and the nonsteroidal anti‐inflammatory drug diclofenac {2‐[2‐(2,6‐dichloroanilino)phenyl]acetic acid, DIC} was discovered. Five solvates of the pharmaceutical salt form were obtained by solid‐form screening. These five multicomponent solvates are the dihydrate (BBR–DIC·2H2O or C20H18NO4+·C14H10Cl2NO2−·2H2O), the dichloromethane hemisolvate dihydrate (BBR–DIC·0.5CH2Cl2·2H2O or C20H18NO4+·C14H10Cl2NO2−·0.5CH2Cl2·2H2O), the ethanol monosolvate (BBR–DIC·C2H5OH or C20H18NO4+·C14H10Cl2NO2−·C2H5OH), the methanol monosolvate (BBR–DIC·CH3OH or C20H18NO4+·C14H10Cl2NO2−·CH3OH) and the methanol disolvate (BBR–DIC·2CH3OH or C20H18NO4+·C14H10Cl2NO2−·2CH3OH), and their crystal structures were determined. All five solvates of BBR–DIC (1:1 molar ratio) were crystallized from different organic solvents. Solvent molecules in a pharmaceutical salt are essential components for the formation of crystalline structures and stabilization of the crystal lattices. These solvates have strong intermolecular O...H hydrogen bonds between the DIC anions and solvent molecules. The intermolecular hydrogen‐bond interactions were visualized by two‐dimensional fingerprint plots. All the multicomponent solvates contained intramolecular N—H...O hydrogen bonds. Various π–π interactions dominate the packing structures of the solvates. [ABSTRACT FROM AUTHOR]

Abstract Lenalidomide (LEN) is a first line drug in the treatment of multiple myeloma, myelodysplastic syndromes, and mantle cell lymphoma. While, this compound holds poor water solubility, leading to unsatisfied bioavailability. To improve the solubility of LEN, a molecular salt with an artificial sweetener, acesulfame (AH), was obtained in this study. The LEN-AH salt was fully characterized by single-crystal and powder X-ray diffraction (XRD), 13C solid state nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), as well as dynamic vapour sorption (DVS). The crystal structure of LEN-AH clearly reveals the intermolecular proton transfer from NH group of AH to NH 2 of LEN. The ionization state of LEN-AH was further confirmed by its feature 13C chemical shifts. The maximum solubility value of LEN was significantly enhanced after salt formation. And the supersaturation state of LEN solution can be maintained at a higher level with the presence of 0.1% PVP-K30. Graphical abstract Image 1 Highlights • Novel pharmaceutical salt form of lenalidomide with acesulfame (LEN-AH) was obtained. • Acesulfame, an artificial sweetener, was used as a salt former. • The maximum solubility value of lenalidomide was significantly improved after salt formation. [ABSTRACT FROM AUTHOR]

• Nine novel salts of domperidone with GRAS coformers have been reported. • SC-XRD revealed the presence of robust + N -H··· O − hydrogen bond. • Increased solubility of DMP in water and 0.1 M HCl in salts. • DMP exhibited faster drug release in purified water in salts. Domperidone (DMP) is an anti-emetic agent used for treatments like dyspepsia, indigestion, epigastric pain, nausea, and vomiting. DMP belongs to BCS class II having poor aqueous solubility and high permeability. In the current work, nine novel salts of DMP with coformers namely acetic acid (ACA), oxalic acid (OXC), Fumaric acid (FMA), Glutaric acid (GLA), Adipic acid (ADA), Saccharin (SAH), Salicylic acid (SAL), 4-Hydroxybenzoic acid (4HBA), and Theophylline-7-acetic acid (THA) have been reported. The crystal structures have been determined by Single-Crystal X-ray Diffraction (SC-XRD). In the SC-XRD study, proton transfer from coformer to piperidine 'N' of DMP was observed in all the salts. The prepared salts were further characterized by spectroscopic (FT-IR), thermal (DSC and TGA), and Powder X-ray Diffraction (PXRD) techniques. The solubility study in purified water (pH=6.5) showed 127 and 51-fold enhancement in DMP-GLA and DMP-ACA salts. The salts namely, DMP-ACA, DMP-GLA, and DMP-SAL disintegrate to parent DMP after attaining equilibrium in water medium. In 0.1 N HCl medium, DMP-ACA, DMP-GLA, DMP-ADA, and DMP-4HBA exhibited a two-fold increment in solubility compared to DMP. The in-vitro dissolution study in purified water showed faster drug release in DMP-ACA, DMP-GLA, and DMP-ADA salts. [Display omitted] [ABSTRACT FROM AUTHOR]

Organic solvent-free process or green chemistry is needed for manufacturing pharmaceutical salts to avoid various environmental, safety, and manufacturing cost issues involved. In this study, a cinnarizine (CNZ) salt with malic acid at a 1:1 molar ratio was successfully prepared by twin screw extrusion (TSE) with water assistance. The feasibility of salt formation was first evaluated by screening several carboxylic acids by neat grinding (NG) and liquid-assisted grinding (LAG) using a mortar and pestle, which indicated that malic acid and succinic acid could form salts with CNZ. Further studies on salt formation were conducted using malic acid. The examination by hot-stage microscopy revealed that the addition of water could facilitate the formation and crystallization of CNZ-malic acid salt even though CNZ is poorly water-soluble. The feasibility of salt formation was confirmed by determining the pH-solubility relationship between CNZ and malic acid, where a pH max of 2.7 and a salt solubility of 2.47 mg/mL were observed. Authentic salt crystals were prepared by solution crystallization from organic solvents for examining crystal properties and structure by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared (FTIR) spectroscopy, solid-state 13 C and 15 N nuclear magnetic resonance (NMR), and single-crystal X-ray diffraction (SXD). These techniques also established that a salt, and not a cocrystal, was indeed formed. The CNZ salt crystals were then prepared by TSE of a 1:1 CNZ-malic acid mixture, where the addition of small amounts of water resulted in a complete conversion of the mixture into the salt form. The salts prepared by solvent crystallization and water-assisted TSE had identical properties, and their moisture sorption profiles were also similar, indicating that TSE is a viable method for salt preparation by green chemistry. Since TSE can be conducted in a continuous manner, the results of the present investigation, if combined with other continuous processes, suggest the possibility of continuous manufacturing of drug products from the synthesis of active pharmaceutical ingredients (APIs) to the production of final dosage forms.

Acyclovir is a commonly used antiviral drug while its solubility is far from satisfied. It was reported that 1:1 acyclovir-maleic acid salt (ACV-MAL) possesses much higher maximum apparent solubility. In this contribution, a new crystal structure of ACV-MAL was solved at room temperature. This new crystal structure and previously reported structure at low temperature can transform to each other via a reversible solid phase transformation, which has been confirmed by single-crystal X-ray diffraction, solid state NMR and cycling differential scanning calorimetry tests. The phase change temperature is ca . 283–293 K (10–20 °C), which is slightly lower than room temperature (298 ± 2 K/25 ± 2 °C), but is in the range of ambient temperature. This kind of near room temperature phase transformation is less concerned and tends to be neglected. This case report reminds that more attention should be paid to the polymorphism of pharmaceuticals at such temperature range due to its fundamental and practical significance. [ABSTRACT FROM AUTHOR]

• A novel salt of BLA with ORA is synthesized and the crystal structure was determined by SC-XRD analysis. • The newly formed salt is thoroughly characterized by various spectroscopic (FT-IR), thermal methods (DSC, TGA, Hot-stage), and PXRD techniques. • A detailed synthetic method is established for the preparation of BLA-ORA. • BLA exhibited enhanced solubility in water as well as 0.1 N HCl medium. Bilastine (BLA) is an European Medicines Agency approved second-generation antihistamine drug used for the treatment of allergic rhinoconjunctivitis and chronic urticarial. The major disadvantage of Bilastine is its poor aqueous solubility. In the present work, the authors describe the novel salt of BLA with orotic acid (ORA) as a counter ion. ORA is a well-known molecule that exhibits important physiological functions and pharmacological characteristics. The newly formed salt is thoroughly characterized by various spectroscopic and thermal methods. The crystal structure determination by Single-Crystal X-ray Diffraction (SC-XRD) techniques revealed the proton transfer from ORA to piperidine nitrogen of BLA. The melting temperature of the obtained salt was found to be in between the melting of BLA and ORA and the salt is found to be thermally stable until melting based on DSC, TGA, and Hot-stage analysis. FT-IR spectroscopy depicts the formation of salt based on –C = O stretching frequencies of both BLA and ORA. A detailed synthetic method is established for the BLA-ORA salt by employing various approaches in different solvents. The solubility study in purified water (pH=6.5) and 0.1 N HCl (pH=1.2) showed an increase of 4 and 1.2 fold respectively when compared with pure BLA drug. [Display omitted] [ABSTRACT FROM AUTHOR]

Pharmaceutical salts had been defined as 'compounds' formed between a molecular or ionic active pharmaceutical substance and a salt former. Like cocrystals, salts are mainly prepared in order to increase the biodisponibility of the active substance. In this paper, we present the formation of a pharmaceutical salt prepared by cocrystallization which was obtained from ketoprofen (KT) and cysteine (Cys). The physicochemical properties of the KT-Cys salt were investigated by thermal analysis, Fourier-transform infrared spectroscopy and powder X-ray diffraction (PXRD) techniques. The heat flow curve of the KT-Cys is different from the ones of KT and Cys and suggests that under experimental conditions, the interaction between the two compounds occurred. This aspect and the corroboration with the results from spectroscopy and PXRD data confirmed the formation of a salt and the absence of any unbound component. [ABSTRACT FROM AUTHOR]

Pharmaceutical salts are ubiquitously present in the market given their benefits in optimizing the critical properties of an active pharmaceutical ingredient (API). Achieving these benefits requires careful selection and understanding of the salt form of choice. Stability is especially critical here, as salts are susceptible to disproportionation. Several studies have shown the impact of moisture on disproportionation, with more focus on external humidity (moisture coming from outside the system). This work, on the other hand, is systematically designed to study the impact of moisture generated in situ (moisture produced within the system). To that end, an in-house developed compound 1 was selected as our salt API, and its disproportionation was studied in blends (binary and prototype) with hydrated model excipient─trisodium phosphate dodecahydrate (TSPD). TSPD possesses 12 water molecules, which could get released when triggered with enough energy (confirmed by thermogravimetric analysis and humidity studies). As a control for this study, similar blends were prepared with anhydrous trisodium phosphate (TSP), which has comparable properties to TSPD but lacks water. Overall, significant disproportionation was observed in TSPD blends exposed to 40 °C or 70 °C in a closed system; while no disproportionation was observed when the system was left open due to the escape of the moisture generated in situ. The API also remained intact for the blends with anhydrous TSP, as expected. Meanwhile, stressing at 40 °C/75%RH condition resulted in significant disproportionation for both TSPD and TSP blends due to the exposure to external humidity. Hydrated excipients are normally used in drug development, and this work stresses the need for probing the impact from within the system when such excipients are utilized with salt API. This will help fully unravel the overall effect of moisture on the drug, which is relevant downstream when selecting processing conditions, packaging, and so forth.

A hydrophilic interaction chromatography (HILIC) method using an aminopropyl stationary phase was developed and validated to determine the content of tromethamine as counter ion in an investigational drug substance. Tromethamine was a very polar compound without any chromophores, and could not be readily retained and detected by conventional reserved-phase HPLC-UV methods. Furthermore, the tromethamine salt of the drug compound also had limited solubility in aqueous solution. The method employed simple acetonitrile/water mobile phase (80/20, v/v) to provide sufficient retention for tromethamine. Meanwhile, the high acetonitrile content also helped to dissolve the drug substance sample. Refractive index (RI) was used for the detection of tromethamine. The method was found to be specific without interference from the drug compound and related impurities. The method was also validated for suitable precision, linearity and accuracy for the analysis of drug substance samples. The effects of various parameters, such as acetonitrile content, mobile phase salt concentration, and column temperature on HILIC separation were investigated. [Copyright &y& Elsevier]

Dasabuvir is a non-nucleoside polymerase inhibitor for the treatment of hepatitis C virus (HCV) infection. It is an extremely weak diacidic drug (p K a = 8.2 and 9.2) and a prolific solvate former. Due to its exceedingly low aqueous solubility (≤0.127 μg/mL at pH 1-6.8, dose number of 1.31 × 10 4 ), crystalline dasabuvir free acid exhibited poor oral bioavailability in initial animal pharmacokinetic (PK) assessment. This necessitated the development of enabling formulation for human clinical studies to achieve the required therapeutic in vivo concentration of dasabuvir. While salt formation has been widely used to enhance the solubility and dissolution rate of solids, this approach has rarely been applied to develop oral solid dosage forms for acidic drugs as weak as dasabuvir due to concerns of rapid disproportionation and crystallization of its free acid. In this contribution, we detail our efforts in identifying dasabuvir monosodium monohydrate as a drug substance that is stable, manufacturable, and, most importantly, significantly enhances the dissolution and oral absorption of this poorly soluble drug. The oral delivery of dasabuvir through the salt approach has enabled the commercialization of the triple-combination direct-acting antiviral HCV regimen, Viekira Pak. The methodologies and solutions identified in targeted studies to overcome technical challenges encountered along the way (i.e., incorporation of polymers to inhibit crystallization and disproportionation and species mapping to enable salt manufacturing process, etc.) can be applied to other insoluble compounds.

• Synthesizing pharmaceutical salt of palmatine (PMT). • Improving the hygroscopic stability of PMTCl by forming pharmaceutical salt. • A unique zipper structure is first observed in pharmaceutical salt of PMT. In order to improve the hygroscopic stability of palmatine chloride (PMTCl) without reducing its solubility, on the basis of summarizing tetrahydroberberine and sulfophenyl acids pharmaceutical cocrystals/salts, we speculated that sodium saccharinate (SACNa), an organic acid salt with the same sulfonyl group, may be cocrystallized with ionic PMT. Consequently, an unreported PMT-SAC (C 21 H 22 NO 4 · C 7 H 4 NO 3 S) pharmaceutical salt was synthesized. The maximum solubility of PMT-SAC in pure water is essentially the same as that of PMTCl. As the hygroscopic stability of PMT-SAC is significantly improved, it is speculated that in the PMT-SAC pharmaceutical salt, PMT cations and SAC anions mainly rely on hydrogen bonds to accumulate, due to the fact that the hydrogen bonds acting between the groups of PMT cations and SAC anions are nearly saturated, it is therefore difficult for PMT cations to combine with external water molecules. This implies that a single crystal of pharmaceutical salt with the desired physicochemical properties will conceivably be obtained for ionic active pharmaceutical ingredients through the introduction of organic acid salts, which are able to form hydrogen bonds. Further to this, it is of note that the antibacterial activities in vitro of a pharmaceutical salt of PMT-SAC is improved, when compared with the corresponding parent compound (PMTCl). Image, graphical abstract [ABSTRACT FROM AUTHOR]

In order to further explore the role of Charge-assisted hydrogen bonds (CAHBs) recognition in the formation of tetrahydroberberine (THB) pharmaceutical salt/cocrystal, based on the analysis of the molecular interactions in forming unit pharmaceutical salts/cocrystal of THB and sulfophenyl acids, we speculate that hydroxyl group of sulfamic acid (SA) may cocrystallize with N atom on the quinoline ring of THB via CAHBs. Consequently, an unreported pharmaceutical salt (C 20 H 22 NO 4 ·NH 2 SO 3 , THB-SA) of the THB was designed and synthesized. The THB-SA was characterized by single crystal X-ray diffraction, XRPD and TG methods. As expected, structure analysis of the THB-SA revealed that the THB molecule binds to the SA molecule precisely through CAHBs (N+-H···O−) between the N atom on the quinoline ring and sulfonic acid group of SA in asymmetric unit of THB-SA. This successfully implemented work implies that in the preparation of THB pharmaceutical salts/cocrystals, cocrystal formers (CCFs) that can form CAHBs with THB should be selected, which will provide a facilitate way to prepare THB pharmaceutical salts/cocrystals. Image 1 • The successful preparation of THB-SA pharmaceutical salt has been verified that the formation mechanism of CAHBs in tetrahydroberberine and sulfamic acid is basically consistent with the formation mechanism of CAHBs in tetrahydroberberine and organic acids. [ABSTRACT FROM AUTHOR]

Salts are generally prepared by acid-base reaction in relatively large volumes of organic solvents, followed by crystallization. In this study, the potential for preparing a pharmaceutical salt between haloperidol and maleic acid by a novel solvent-free method using a twin-screw melt extruder was investigated. The pH-solubility relationship between haloperidol and maleic acid in aqueous medium was first determined, which demonstrated that 1:1 salt formation between them was feasible (pH max 4.8; salt solubility 4.7 mg/mL). Extrusion of a 1:1 mixture of haloperidol and maleic acid at the extruder barrel temperature of 60 °C resulted in the formation of a highly crystalline salt. The effects of operating temperature and screw configuration on salt formation were also investigated, and those two were identified as key processing parameters. Salts were also prepared by solution crystallization from ethyl acetate, liquid-assisted grinding, and heat-assisted grinding and compared with those obtained by melt extrusion by using DSC, PXRD, TGA, and optical microscopy. While similar salts were obtained by all methods, both melt extrusion and solution crystallization yielded highly crystalline materials with identical enthalpies of melting. During the pH-solubility study, a salt hydrate form was also identified, which, upon heating, converted to anhydrate similar to that obtained by other methods. There were previous reports of the formation of cocrystals, but not salts, by melt extrusion. 1 H NMR and single-crystal X-ray diffraction confirmed that a salt was indeed formed in the present study. The haloperidol-maleic acid salt obtained was nonhygroscopic in the moisture sorption study and converted to the hydrate form only upon mixing with water. Thus, we are reporting for the first time a relatively simple and solvent-free twin-screw melt extrusion method for the preparation of a pharmaceutical salt that provides material comparable to that obtained by solution crystallization and is amenable to continuous manufacturing and easy scale up.

There is a paucity of data describing the impact of salt counterions on the biological performance of inhaled medicines in vivo. The aim of this study was to determine if the coadministration of salt counterions influenced the tissue permeability and airway smooth muscle relaxation potential of salbutamol, formoterol, and salmeterol. The results demonstrated that only salbutamol, when formulated with an excess of the 1-hydroxy-2-naphthoate (1H2NA) counterion, exhibited a superior bronchodilator effect (p < 0.05) compared to salbutamol base. The counterions aspartate, maleate, fumarate, and 1H2NA had no effect on the ability of formoterol or salmeterol to reduce airway resistance in vivo. Studies using guinea pig tracheal sections showed that the salbutamol:1H2NA combination resulted in a significantly faster (p < 0.05) rate of tissue transport compared to salbutamol base. Furthermore, when the relaxant activity of salbutamol was assessed in vitro using electrically stimulated, superfused preparations of guinea pig trachea, the inhibition of contraction by salbutamol in the presence of 1H2NA was greater than with salbutamol base (a total inhibition of 94.13%, p < 0.05). The reason for the modification of salbutamol's behavior upon administration with 1H2NA was assigned to ion-pair formation, which was identified using infrared spectroscopy. Ion-pair formation is known to modify a drug's physicochemical properties, and the data from this study suggested that the choice of counterion in inhaled pharmaceutical salts should be considered carefully as it has the potential to alter drug action in vivo.