Hydrochloride Salt Form Research Articles

Low-frequency Raman spectrum of methamphetamine hydrochloride and its alterations induced by impurities

Methamphetamine is one of the most abused drugs worldwide. Forensic laboratories have developed various methods to analyze methamphetamine for identifying and comparing seizures. These methods basically focus on the physicochemical properties of the methamphetamine molecule. Because methamphetamine is commonly distributed in its hydrochloride salt form, information on the crystalline state of methamphetamine could give new insight for forensic drug analysis. To grasp this information, we applied low-frequency Raman spectroscopy to methamphetamine hydrochloride. A laboratory-built low-frequency Raman microspectrometer was used for measuring low-frequency Raman spectra of optically pure and racemic methamphetamine hydrochloride. A mixture of methamphetamine hydrochloride with dimethyl sulfone, which is frequently added as a diluent to illicit methamphetamines, was also measured. An ab initio calculation was performed to assign peaks in the low-frequency spectra. The phonon modes of methamphetamine hydrochloride, and their changes induced by impurities are discussed. To the best of our knowledge, this is the first reported application of low-frequency Raman spectroscopy technique to methamphetamine hydrochloride.

Design, Synthesis, and Characterization of Novel Thiazolidine-2,4-Dione-Acridine Hybrids as Antitumor Agents.

This study focuses on the synthesis and structural characterization of new compounds that integrate thiazolidine-2,4-dione, acridine moiety, and an acetamide linker, aiming to leverage the synergistic effects of these pharmacophores for enhanced therapeutic potential. The newly designed molecules were efficiently synthesized through a multi-step process and subsequently transformed into their hydrochloride salts. Comprehensive spectroscopic techniques, including nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), infrared (IR) spectroscopy, and elemental analysis, were employed to determine the molecular structures of the synthesized compounds. Biological evaluations were conducted to assess the therapeutic potential of the new compounds. The influence of these derivatives on the metabolic activity of various cancer cell lines was assessed, with IC50 values determined via MTT assays. An in-depth analysis of the structure-activity relationship (SAR) revealed intriguing insights into their cytotoxic profiles. Compounds with electron-withdrawing groups generally exhibited lower IC50 values, indicating higher potency. The presence of the methoxy group at the linking phenyl ring modulated both the potency and selectivity of the compounds. The variation in the acridine core at the nitrogen atom of the thiazolidine-2,4-dione core significantly affects the activity against cancer cell lines, with the acridin-9-yl substituent enhancing the compounds' antiproliferative activity. Furthermore, compounds in their hydrochloride salt forms demonstrated better activity against cancer cell lines compared to their free base forms. Compounds 12c·2HCl (IC50 = 5.4 ± 2.4 μM), 13d (IC50 = 4.9 ± 2.9 μM), and 12f·2HCl (IC50 = 4.98 ± 2.9 μM) demonstrated excellent activity against the HCT116 cancer cell line, and compound 7d·2HCl (IC50 = 4.55 ± 0.35 μM) demonstrated excellent activity against the HeLa cancer cell line. Notably, only a few tested compounds, including 7e·2HCl (IC50 = 11.00 ± 2.2 μM), 7f (IC50 = 11.54 ± 2.06 μM), and 7f·2HCl (IC50 = 9.82 ± 1.92 μM), showed activity against pancreatic PATU cells. This type of cancer has a very high mortality due to asymptomatic early stages, the occurrence of metastases, and frequent resistance to chemotherapy. Four derivatives, namely, 7e·2HCl, 12d·2HCl, 13c·HCl, and 13d, were tested for their interaction properties with BSA using fluorescence spectroscopic studies. The values for the quenching constant (Ksv) ranged from 9.59 × 104 to 10.74 × 104 M-1, indicating a good affinity to the BSA protein.

One-Flow Operation via 4-Bromopyridine Enables Flash Synthesis of AChE Inhibitor

Abstract4-Bromopyridine is a building block that can be converted into valuable compounds, but due to its low stability, it is commercially available in the form of hydrochloride salt. Therefore, the hydrochloride salt is usually desalted with a basic aqueous solution and dried before organic reaction. In this study, to simplify the preparation and reaction procedure of 4-bromopyridine, multiple operations, desalting with a base, separation of the aqueous layer, and subsequent halogen–lithium exchange reaction were integrated into a single flow reaction. The reaction sequence was completed within 20 seconds and the yields were higher than the conventional methods. This is because the subsequent reaction can be performed immediately after the generation of 4-bromopyridine, which is unstable under ambient conditions.

A comprehensive evaluation of arginine and its derivatives as protein formulation stabilizers

Arginine and its derivatives (such as arginine ethyl ester and acetyl arginine) have varying degrees of protein aggregation suppressor effect across different protein solutions. To understand this performance ambiguity, we evaluated the activity of arginine, acetyl arginine, and arginine ethyl ester for aggregation suppressor effect against human intravenous immunoglobulin G (IgG) solution at pH 4.8. Both arginine and its cationic derivative arginine ethyl ester in their hydrochloride salt forms significantly reduced the colloidal and conformational stability (reduced kd and Tm) of IgG. Consequently, the monomer content was decreased with an increase in subvisible particulates after agitation or thermal stress. Furthermore, compared to arginine, arginine ethyl ester with one more cationic charge and hydrochloride salt form readily precipitated IgG at temperatures higher than 25 °C. On the contrary, acetyl arginine, which mostly exists in a neutral state at pH 4.8, efficiently suppressed the formation of subvisible particles retaining a high amount of monomer owing to its higher colloidal and conformational stability. Concisely, the charged state of additives significantly impacts protein stability. This study demonstrated that contrary to popular belief, arginine and its derivatives may either enhance or suppress protein aggregation depending on their net charge and concentration.

Amorphous solid dispersions of lidocaine and lidocaine HCl produced by ball milling with well-defined RAFT-synthesised methacrylic acid polymers

This study focuses on the use of methacrylic acid polymers synthesised via the Reversible Addition Fragmentation chain Transfer (RAFT) polymerisation method for the production of amorphous solid dispersions (ASDs) by ball milling, to kinetically solubilize a poorly water-soluble model drug. The solid-state characteristics and the physical stability of the formulations were investigated using X-ray diffraction, differential scanning calorimetry, and infrared spectroscopy. This was followed by dissolution studies in different media. It was discovered that the acidic polymers of methacrylic acid were capable of interacting with the weakly basic drug lidocaine and its hydrochloride salt form to produce ASDs when a polymer to drug ratio of 70:30 w/w was used. The ASDs remained amorphous following storage under accelerated aging conditions (40 °C and 75% relative humidity) over 8 months. Fast dissolution and increased lidocaine solubility in different media were obtained from the ASDs owing to the reduced microenvironment pH and enhanced solubilization of the drug caused by the presence of the acidic polymer in the formulation. Production of ASDs using well-defined RAFT-synthesised acidic polymers is a promising formulation strategy to enhance the pharmaceutical properties of basic poorly water-soluble drugs.

The free hydralazine anti-hypertensive drug and new salts with improved solubility

Although long used as an antihypertensive drug because of its vasodilator properties, Hydralazine (HDZ) has received renewed attention in the last few years due to its secondary therapeutic effects, which has led to its repurposing for its antioxidative, anti-apoptotic, and anti-inflammatory abilities, especially in cardiovascular and renal diseases. Given the worldwide prevalence of these diseases and that only the hydrochloride salt form of this drug has been reported and commercialized until now, in this paper we describe the synthesis, crystalline structure and physicochemical properties of the free hydralazine and its two new salts, a bromide (HDZ-Br) and a nitrate (HDZ-NO3), aiming to provide new candidates of HDZ solid forms that can be potentially used as an alternative to the pattern antihypertensive treatment, with better properties than the commercial one and can also be used in new applications addressed to this drug. Herein we investigated the three new multicomponent solid forms using single crystal X-ray diffraction (SCXRD), X-ray powder diffraction (XRPD), Differential Scanning Calorimetry (DSC), Thermogravimetric analysis (TGA), Infrared/Raman spectroscopies, and relative solubility studies. Interestingly, all structures showed the formation of HDZ columns intercalated with ions columns as well as a strong tendency to develop π···π stacking interactions among HDZ molecules which can be useful for future design of new potential multicomponent forms of HDZ. The new reported salts show a relative solubility higher than the commercially hydralazine hydrochloride form, suggesting that they can be potentially useful in new pharmaceutical formulations.

Does the salt really matter? Impact of the counterion upon ECL signal

The incorporation of counterions into a variety of substances to control a number of their physiochemical properties is vital within a range of fields. Electrochemiluminescence (ECL) based sensors have grown in popularity in recent years with their employment observed across analytical and bioanalytical applications. ECL is typically concerned with the core electroactive functionality of the species of interest, with structural similarities commonly employed to determine the likelihood of a species ECL capability. However, to date no consideration has been given to the impact of different counterions toward an analytes ECL mechanism. Here we report for the first time how a simple alternation to a co-reactants counterion can significantly impact upon its recorded ECL response. Utilizing the tropane alkaloid scopolamine and its hydrobromide and hydrochloride salt forms, we have seen through interrogation with the traditional ruthenium luminophore, that replacement of the bromide anion for the chloride anion can reduce the electroactivity of the species. Direct comparison between the hydrobromide and hydrochloride salt forms relived differences in respect of their emission potentials and intensities. The impact of the salt form upon the ECL response has here been investigated, in respect to predicted concentrations. Results demonstrated how vastly different concentrations were obtained dependent upon the salt form present within the sample and that which was used to produce the calibration curve. The impact of this discovery will be of interest to the electrochemiluminescent and electroanalytical communities, and in particular forensic practitioners where electrochemical and ECL based sensors are of increasing interest. Ultimately the application of an ECL sensor within an analytical environment relies upon its accuracy and hence a thorough understanding of the phenomenon observed will only stand to widen the acceptance of ECL within the wider analytical community and increase its potential future applications.

Evaluation of pyrrolidine-based analog of jaspine B as potential SphK1 inhibitors against rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovitise, and its pathogenesis is complicated. Sphingosine-1-phosphate (S1P) is a lipid produced by sphingosine kinase 1 and 2 (SphK1/2), which participate in some of most-spread skeletal diseases such as rheumatoid arthritis or osteoarthritis. To explore the anti-inflammatory activity of 2-epi-jaspine B analogs as SphKs inhibitors, we used LPS-induced rheumatoid arthritis fibroblast-like synovial cells (HFLS-RA) as the research object to evaluate the anti-inflammatory activity of 16 2-epi-jaspine B analogs and the newly synthesized salt CHJ01. We found that 2-epi-jaspine B analog CHJ01 in hydrochloride salt form has excellent SphK1 inhibitory effect and better anti-RA effect. CHJ01 showed an anti-inflammatory effect similar to that of MTX in vitro, its IC50 value is 8.64 μM. Moreover, the anti-RA effect of CHJ01 was also studied by using a Complete Freund’s Adjuvant (CFA)-induced arthritis (AIA) in a rat mode. Pharmacological experiments show that CHJ01 can help to significantly improve the symptoms of rheumatoid arthritis by reducing the swelling volume, arthritis score, spleen index and the level of IL-1β, TNF-α, IL-6 of AIA rats. Therefore, CHJ01 holds high potential for the treatment of RA.

Efficient synthesis and antitumor evaluation of 4-aminomethyl-N-arylpyrazoles: Discovery of potent and selective agents for ovarian cancer

A new one-pot two-step sequential methodology for synthesis of novel 3-carboxyethyl 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives is reported. One-pot transformation of β-enamino diketones and arylhydrazines generated 4-iminium-N-arylpyrazole salt intermediates in situ, which were easily transformed into 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives by NaBH3CN. The products could be isolated in the free or hydrochloride salt forms. Also, it was possible to obtain the products in the zwitterionic form by ester group hydrolysis. Furthermore, all synthesised compounds were evaluated in vitro against a panel of eight human tumor cell lines. The 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives were much more powerful than the hydrochloride and zwitterionic forms. Moreover, the results suggest that the N-aryl group at the pyrazole ring is vital for modulating antiproliferative activity. The 3-carboxyethyl 4-[(tert-butylamino)methyl]-N-phenylpyrazoles 3a–g exhibited higher inhibitory activities against OVCAR-3, with GI50 values of 0.013–8.78 μM, and lower inhibitory activities against normal human cell lines. Molecular docking was performed to evaluate the probable binding mode of 3a into active site of CDK2.

Targeting Endoplasmic Reticulum α-Glucosidase I with a Single-Dose Iminosugar Treatment Protects against Lethal Influenza and Dengue Virus Infections.

Influenza and dengue viruses present a growing global threat to public health. Both viruses depend on the host endoplasmic reticulum (ER) glycoprotein folding pathway. In 2014, Sadat et al. reported two siblings with a rare genetic defect in ER α-glucosidase I (ER Glu I) who showed resistance to viral infections, identifying ER Glu I as a key antiviral target. Here, we show that a single dose of UV-4B (the hydrochloride salt form of N-(9'-methoxynonyl)-1-deoxynojirimycin; MON-DNJ) capable of inhibiting Glu I in vivo is sufficient to prevent death in mice infected with lethal viral doses, even when treatment is started as late as 48 h post infection. The first crystal structure of mammalian ER Glu I will constitute the basis for the development of potent and selective inhibitors. Targeting ER Glu I with UV-4B-derived compounds may alter treatment paradigms for acute viral disease through development of a single-dose therapeutic regime.

RP-HPLC Method for Estimation of Daclatasvir in Bulk and Tablet Dosage Form

A new simple accurate precise RP-HPLC method for the quantitative determination of Daclatasvir was developed and validated as per ICH guidelines for the parameters like accuracy precision robustness repeatability LOD and LOQ. Daclatasvir is a direct-acting antiviral agent against Hepatitis C Virus HCV used for the treatment of chronic HCV genotype 1 and 3 infection. It is marketed under the name DAKLINZA and in daily oral tablets as the hydrochloride salt form. The drug was injected into Denali C8 250mm4.6mm 5micro maintained at ambient temperature and effluent monitored at 304 nm. Different mobile phase compositions were trailed out of which the mobile phase consisting of 0.01N KH2 PO4 Acetonitrile in the ratio of 5050 VV was selected as optimized because it has given sharp peak with good resolution. The flow rate was maintained at 1.0 mlm. The calibration curve for Daclatasvir was linear from 15-90 microgml r2 for Daclatasvir0.999. The proposed method was adequate sensitive reproducible accurate and precise for the determination of Daclatasvir in bulk and pharmaceutical dosage forms.

Determination of Dimethylamine and Triethylamine in Hydrochloride Salts of Drug Substances by Headspace Gas Chromatography using Dimethyl Sulphoxide- imidazole as Diluent

A simple, rapid, accurate and precise analytical method for determination of secondary and tertiary amines in hydrochloride salt form of drug substances in non aqueous medium, which does not require any derivatization, was developed by headspace gas chromatography. Dimethylamine hydrochloride and triethylamine hydrochloride were analyzed in metformin hydrochloride. The sample was dissolved in a vial containing dimethyl sulphoxide and imidazole. The vials were incubated at 100o, for 20 min. The syringe temperature was maintained at 110o. DB624 column with 30 m×0.32 mm i.d., 1.8 µm film thickness was used. The injector and detector temperature were 200° and 250°, respectively. The analytical program used was carrier gas (nitrogen) flow rate: 1 ml/min; injected gas volume: 1.0 ml; split ratio: 1:10; oven temperature program: 40o for 10 min, followed by an increase up to 240° at 40o/min. The analytical method was validated with respect to precision, recovery, limit of detection and quantification and linearity.

Vibrational Circular Dichroism (VCD) Reveals Subtle Conformational Aspects and Intermolecular Interactions in the Carnitine Family.

Vibrational circular dichroism spectra (VCD) in the mid-IR region and electronic circular dichroism (ECD) spectra for three carnitine derivatives in the form of hydrochloride salts were recorded in deuterated methanol solutions. Density Functional Theory calculations help one to understand the significance of the observed VCD bands. VCD and ECD spectra are informative about the absolute configuration of the molecule, but VCD data reveal also some conformational aspects in the N,N,N-trimethyl moiety and inform us about intermolecular interactions gained from the carbonyl stretching region for the acyl substituted carnitines.

The hydrochloride and hydrobromide salt forms of (S)-amphetamine.

Despite the high profile of amphetamine, there have been relatively few structural studies of its salt forms. The lack of any halide salt forms is surprising as the typical synthetic route for amphetamine initially produces the chloride salt. (S)-Amphetamine hydrochloride [systematic name: (2S)-1-phenylpropan-2-aminium chloride], C9H14N(+)·Cl(-), has a Z' = 6 structure with six independent cation-anion pairs. That these are indeed crystallographically independent is supported by different packing orientations of the cations and by the observation of a wide range of cation conformations generated by rotation about the phenyl-CH2 bond. The supramolecular contacts about the anions also differ, such that both a wide variation in the geometry of the three N-H...Cl hydrogen bonds formed by each chloride anion and differences in C-H...Cl contacts are apparent. (S)-Amphetamine hydrobromide [systematic name: (2S)-1-phenylpropan-2-aminium bromide], C9H14N(+)·Br(-), is broadly similar to the hydrochloride in terms of cation conformation, the existence of three N-H...X hydrogen-bond contacts per anion and the overall two-dimensional hydrogen-bonded sheet motif. However, only the chloride structure features organic bilayers and Z' > 1.

Design and Synthesis of new Nanosized C 3-Symmetrical Tricarboxylic Acids: Key Elongated Ligands for the Preparation of Highly Porous MOFs

The synthesis of two new <i>C</i> ₃-symmetrical nanosized tricarboxylic acids bearing triphenylmethane cores and three imines linkages is presented. The new elongated tripods were designed to stabilise highly porous metal-organic frameworks (MOFs) and were synthesized by a threefold Schiff base condensation reaction between the reduced leuco form of pararosaniline hydrochloride salt and an appropriate aldehyde.

Solid state structure of new 5-[2-(N,N-diethylamino)ethoxy]-4,7-dimethylcoumarins by X-ray and 13C CP/MAS NMR

5-[2-(N,N-diethylamino)ethoxy]-4,7-dimethylcoumarin (1) and 6-acetyl-5-[2-(N,N-diethylamino)ethoxy]-4,7-dimethylcoumarin (2) were synthesized in a traditional way and microwave-assisted synthesis. Crystals of 2 in form of hydrochloride salt (3) were investigated using single crystal X-ray diffraction technique. In the crystal lattice of 3 there is only one type of strong hydrogen bond present involving protonated amino group and chloride anion. The whole structure is dominated by weak C–H…Cl−, C–H…O contacts. There is also visible aggregation of cations in stacks due to π–π interactions. The solid state structures of 1 and 2 derived from 13C CP/MAS NMR spectra were also proposed.

Solid-state characterization of sertraline base–β-cyclodextrin inclusion complex

Sertraline is one of the serotonin-specific reuptake inhibitors that is effective in treating several disorders such as major depression, obsessive–compulsive disorder, panic disorder, and social phobia. It is marketed in the form of its hydrochloride salt, which exhibits better solubility in water than its free base form. However, the absorption of sertraline through biological membranes could be improved by enhancing the solubility of its base because it is more hydrophobic than sertraline hydrochloride. To clarify the mechanism for the interaction of sertraline base with β-CD, it is important to study the basic interaction between the β-CD ring and sertraline base. Therefore, in this study, the currently used hydrochloride salt form was converted into the free base and β-CD was used as a model for β-CD derivatives to evaluate the interaction between β-CD and the sertraline base. The solid-state physicochemical characteristics of the sertraline–β-CD complex were investigated by the phase solubility method, differential scanning calorimetry, Fourier transform IR spectroscopy, FT-Raman spectroscopy, powder X-ray diffraction, and 13C cross-polarization magic-angle spinning NMR measurements. The results showed that sertraline base and β-CD form an inclusion complex, and the stoichiometric ratio of the solid-state sertraline base–β-CD complex is 1:1, which was estimated by the 1H NMR measurements of the complex dissolved in DMSO-d6.

Antimosquito Properties of 2-Substituted Phenyl/benzylamino-6-(4- chlorophenyl)-5-methoxycarbonyl-4-methyl-3,6-dihydropyrimidin-1-ium Chlorides Against Anopheles arabiensis

Eight novel dihydropyrimidine analogs named DHPM1-DHPM8 was synthesized in their hydrochloride salt form using one pot synthesis between methyl 2-chloro-4-(4-chlorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate and substituted arylamines in isopropanol. The antimosquito effect of the test compounds were assessed against the adult mosquito Anopheles arabiensis. For adulticidal properties the test compounds were sprayed onto ceramic tiles and screened using the cone bio-assay method. The larvicidal activity was tested by monitoring larval mortality daily and up to 3 days of exposure. Repellency properties were tested in a feeding-probe assay using unfed female Anopheles arabiensis. Compounds DHPM1, DHPM4, DHPM5 and DHPM6 exerted larval mortality equivalent to temephos (trade name Abate, a commercial larvicidal compound). Compounds DHPM1 to DHPM5 repelled or knocked down 92 to 98% of mosquitoes exposed to rodent skin treated with the compounds. None of the compounds showed any significant activity against the adult mosquito Anopheles arabiensis.

Synthesis and Antitubercular Activity of 2‐(substituted phenyl/benzyl‐amino)‐6‐(4‐chlorophenyl)‐5‐(methoxycarbonyl)‐4‐methyl‐3,6‐dihydropyrimidin‐1‐ium Chlorides

A series of 2-(substituted phenyl/benzyl-amino)-6-(4-chlorophenyl)-5-(methoxycarbonyl)-4-methyl-3,6-dihydropyrimidin-1-ium chlorides 7-13 and 15 was synthesized in their hydrochloride salt form. The title compounds were characterized by FT-IR, NMR ((1)H and (13)C) and elemental analysis. They were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv, multidrug resistance tuberculosis and extensively drug resistance tuberculosis by agar diffusion method and tested for the cytotoxic action on peripheral blood mononuclear cells by MTT assay. Among all the tested compounds in the series, compounds 7 and 11 emerged as promising antitubercular agents at 16 μg/mL against multidrug resistance tuberculosis and over 64 μg/mL against extensively drug resistance tuberculosis. The conformational features and supramolecular assembly of the promising compounds 7 and 11 were determined by single crystal X-ray study.

Validated LC-MS/MS Method for the Determination of Mirodenafil in Rat Plasma and its Application to a Comparative Pharmacokinetic Study of the Free Base and Hydrochloride Salt Forms of Mirodenafil

In this study, the pharmacokinetics of 2 forms of mirodenafil, namely the base form and the hydrochloride salt form, were investigated in rats. The 2 forms were orally administered to rats and the plasma concentrations of mirodenafil were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The mirodenafil base and hydrochloride salt forms showed similar pharmacokinetic profiles in terms of their maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC). The time to peak concentration (Tmax) of the base form was slightly greater than that of the salt form, but this difference was not statistically significant. These results suggest that the mirodenafil base and hydrochloride forms are pharmacokinetically equivalent in rats, and thus the base form could be used in various mirodenafil formulations as a substitute for the existing mirodenafil hydrochloride form.