Insoluble Salt Forms and Drug Complexes

2000 ◽  
pp. 41-70 ◽  
Author(s):  
Judy Senior
Keyword(s):  
Salt Forms ◽  
Insoluble Salt

scholarly journals Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations

Molecules ◽  
2018 ◽  
Vol 23 (7) ◽  
pp. 1719 ◽  
Author(s):  
Deepak Gupta ◽  
Deepak Bhatia ◽  
Vivek Dave ◽  
Vijaykumar Sutariya ◽  
Sheeba Varghese Gupta
Keyword(s):  
Selection Criteria ◽  
Opposite Effect ◽  
Biological Properties ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Salt Form ◽  
Pharmaceutical Ingredients ◽  
Selection Processes ◽  
Salt Selection ◽  
Pharmaceutical Properties ◽  
Salt Forms

The physicochemical and biological properties of active pharmaceutical ingredients (APIs) are greatly affected by their salt forms. The choice of a particular salt formulation is based on numerous factors such as API chemistry, intended dosage form, pharmacokinetics, and pharmacodynamics. The appropriate salt can improve the overall therapeutic and pharmaceutical effects of an API. However, the incorrect salt form can have the opposite effect, and can be quite detrimental for overall drug development. This review summarizes several criteria for choosing the appropriate salt forms, along with the effects of salt forms on the pharmaceutical properties of APIs. In addition to a comprehensive review of the selection criteria, this review also gives a brief historic perspective of the salt selection processes.

Neutral 4-phenyl-1-[phenyl(pyridin-2-yl)methylidene]semicarbazide and its salt forms with inorganic anions

2019 ◽  
Vol 75 (1) ◽  
pp. 1-7
Author(s):  
Vinicius Oliveira Araujo ◽  
Bárbara Tirloni ◽  
Lívia Streit ◽  
Vânia Denise Schwade
Keyword(s):  
Solid State ◽  
Spectroscopic Characterization ◽  
Water Molecules ◽  
Keto Form ◽  
Chloride Dihydrate ◽  
Ir And Nmr Spectroscopy ◽  
Tautomeric Forms ◽  
Counter Ions ◽  
Salt Forms ◽  
Good Agreement

Semicarbazones can exist in two tautomeric forms. In the solid state, they are found in the keto form. This work presents the synthesis, structures and spectroscopic characterization (IR and NMR spectroscopy) of four such compounds, namely the neutral molecule 4-phenyl-1-[phenyl(pyridin-2-yl)methylidene]semicarbazide, C19H16N4O, (I), abbreviated as HBzPyS, and three different hydrated salts, namely the chloride dihydrate, C19H17N4O+·Cl−·2H2O, (II), the nitrate dihydrate, C19H17N4O+·NO3 −·2H2O, (III), and the thiocyanate 2.5-hydrate, C19H17N4O+·SCN−·2.5H2O, (IV), of 2-[phenyl({[(phenylcarbamoyl)amino]imino})methyl]pyridinium, abbreviated as [H2BzPyS]+·X −·nH2O, with X = Cl− and n = 2 for (II), X = NO3 − and n = 2 for (III), and X = SCN− and n = 2.5 for (IV), showing the influence of the anionic form in the intermolecular interactions. Water molecules and counter-ions (chloride or nitrate) are involved in the formation of a two-dimensional arrangement by the establishment of hydrogen bonds with the N—H groups of the cation, stabilizing the E isomers in the solid state. The neutral HBzPyS molecule crystallized as the E isomer due to the existence of weak π–π interactions between pairs of molecules. The calculated IR spectrum of the hydrated [H2BzPyS]+ cation is in good agreement with the experimental results.

scholarly journals Mixed Ca/Sr salt forms of salicylic acid: tuning structure and aqueous solubility

2018 ◽  
Vol 74 (2) ◽  
pp. 131-138 ◽  
Author(s):  
Pamela Allan ◽  
Jean-Baptiste Arlin ◽  
Alan R. Kennedy ◽  
Aiden Walls
Keyword(s):  
Salicylic Acid ◽  
Coordination Polymer ◽  
Single Crystal ◽  
Structural Feature ◽  
Structural Changes ◽  
Aqueous Solubility ◽  
Single Crystal Diffraction ◽  
One Dimensional ◽  
The One ◽  
Salt Forms

Ten isostructural single-crystal diffraction studies of mixed cation Ca/Sr salt forms of the salicylate anion are presented, namely catena-poly[[diaquacalcium(II)/strontium(II)]-bis(μ2-2-hydroxybenzoato)], [Ca1–x Sr x (C7H5O3)2(H2O)2] n , where x = 0, 0.041, 0.083, 0.165, 0.306, 0.529, 0.632, 0.789, 0.835 and 1. The structure of an isostructural Sr/Ba species, namely catena-poly[[diaquastrontium(II)/barium(II)]-bis(μ2-2-hydroxybenzoato)], [Sr0.729Ba0.271(C7H5O3)2(H2O)2], is also described. The Ca/Sr structures form a series where, with increasing Sr content, the unit cell expands in both the crystallographic a and c directions (by 1.80 and 3.18%, respectively), but contracts slightly in the b direction (−0.31%). The largest percentage structural expansion lies parallel to the direction of propagation of the one-dimensional coordination polymer that is the primary structural feature. This structural expansion is thus associated with increased M—O distances. Aqueous solubility measurements show that solubility generally increases with increasing Sr content. Thus, tuning the composition of these mixed counter-ion salt forms leads to systematic structural changes and allows solubility to be tuned to values between those for the pure Ca and Sr species.

Multidrug salt forms of norfloxacin with non-steroidal anti-inflammatory drugs: solubility and membrane permeability studies

CrystEngComm ◽  
2018 ◽  
Vol 20 (41) ◽  
pp. 6420-6429 ◽  
Author(s):  
Biswajit Bhattacharya ◽  
Amit Mondal ◽  
Saundray Raj Soni ◽  
Susobhan Das ◽  
Surojit Bhunia ◽  
...  
Keyword(s):  
Membrane Permeability ◽  
Mefenamic Acid ◽  
Dissolution Properties ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Permeability Studies ◽  
Salt Forms

Dissolution properties and membrane permeability studies were conducted for four newly prepared multidrug salts of norfloxacin with four NSAIDs, diclofenac, diflunisal, mefenamic acid and indomethacin.

scholarly journals Structural motifs in salts of sulfathiazole: implications for design of salt forms in pharmaceuticals APIs

CrystEngComm ◽  
2018 ◽  
Vol 20 (24) ◽  
pp. 3428-3434
Author(s):  
Colin C. Seaton ◽  
Rayan R. Thomas ◽  
Eman A. A. Essifaow ◽  
Elisa Nauha ◽  
Tasnim Munshi ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Crystal Packing ◽  
Active Pharmaceutical Ingredients ◽  
Structural Motifs ◽  
Pharmaceutical Ingredients ◽  
The Creation ◽  
Salt Forms

The creation of salts is a frequently used approach to modify physicochemical properties of active pharmaceutical ingredients. This work prepares a collection of sulfathiazole salts to probe the influence of counterion structure on crystal packing.

Pharmaceutical salts of emoxypine with dicarboxylic acids

2018 ◽  
Vol 74 (7) ◽  
pp. 797-806 ◽  
Author(s):  
Alex N. Manin ◽  
Alexander P. Voronin ◽  
Ksenia V. Drozd ◽  
Andrei V. Churakov ◽  
German L. Perlovich
Keyword(s):  
Density Functional Theory ◽  
Density Functional ◽  
Dicarboxylic Acids ◽  
Lattice Energy ◽  
State Density ◽  
Functional Theory ◽  
One Dimensional ◽  
Fusion Enthalpy ◽  
Pharmaceutical Salts ◽  
Salt Forms

New salt forms of the antioxidant drug emoxypine (EMX, 2-ethyl-6-methylpyridin-3-ol) with pharmaceutically acceptable maleic (Mlt), malonic (Mln) and adipic (Adp) acids were obtained {emoxypinium maleate, C8H12NO+·C4H3O4 −, [EMX+Mlt], emoxypinium malonate, C8H12NO+·C3H3O4 −, [EMX+Mln], and emoxypinium adipate, C8H12NO+·C6H9O4 −, [EMX+Adp]} and their crystal structures determined. The molecular packing in the three EMX salts was studied by means of solid-state density functional theory (DFT), followed by QTAIMC (quantum theory of atoms in molecules and crystals) analysis. It was found that the major contribution to the packing energy comes from pyridine–carboxylate and hydroxy–carboxylate heterosynthons forming infinite one-dimensional ribbons, with [EMX+Adp] additionally stabilized by hydrogen-bonded C(9) chains of Adp− ions. The melting processes of the [EMX+Mlt] (1:1), [EMX+Mln] (1:1) and [EMX+Adp] (1:1) salts were studied and the fusion enthalpy was found to increase with the increase of the calculated lattice energy. The dissolution process of the EMX salts in buffer (pH 7.4) was also studied. It was found that the formation of binary crystals of EMX with dicarboxylic acids increases the EMX solubility by more than 30 times compared to its pure form.

Comparisons of 17 lots of 2-oxoglutarate, and specifications for use of this substrate in reference methods.

1985 ◽  
Vol 31 (6) ◽  
pp. 812-818
Author(s):  
P N Bowers ◽  
G N Bowers ◽  
R B McComb
Keyword(s):  
Catalytic Activity ◽  
Liquid Chromatography ◽  
Glutamate Dehydrogenase ◽  
Spectral Characteristics ◽  
Poor Quality ◽  
Activity Concentrations ◽  
Reference Methods ◽  
Specific Analysis ◽  
Quality Material ◽  
Salt Forms

Abstract We examined 17 lots of 2-oxoglutarate (seven acid forms, three K salt forms, and seven Na salt forms), obtained from eight commercial suppliers, for suitability for measuring aspartate aminotransferase (EC 2.6.1.1) and alanine aminotransferase (EC 2.6.1.2) in human serum. Measurements of the catalytic activity concentrations of these two aminotransferases with each of these 17 preparations were not sufficiently sensitive to distinguish good from poor-quality material. Thus, we ranked these lots for purity, by specific analysis with glutamate dehydrogenase and by liquid chromatography, and determined the water content, acid content, and spectral characteristics of each. On the basis of a 2-oxoglutarate assay value by glutamate dehydrogenase of 98% or greater, we considered seven of the preparations acceptable and 10 unacceptable. The molar absorptivities (L X mol-1 X cm-1, mean +/- SD) of the seven acceptable lots in 1 mol/L HCl were: epsilon 325 nm = 9.12 +/- 0.02 (CV = 0.2%), epsilon 279 nm = 2.63 +/- 0.23 (CV = 9.9%), and epsilon 245 nm = 37.9 +/- 4.1 (CV = 10.9%). Use of these spectrophotometric limits alone unambiguously distinguished the inferior lots of 2-oxoglutarate. We urge the inclusion of detailed spectrophotometric specifications for 2-oxoglutarate in Reference Methods for aminotransferase measurements.

2. On the Extraction of pure Phosphoric Acid from Bones, and on a New and Anomalous Phosphate of Magnesia.

1851 ◽  
Vol 2 ◽  
pp. 25-26
Author(s):  
Gregory
Keyword(s):  
Phosphoric Acid ◽  
Sulphuric Acid ◽  
Colourless Glass ◽  
Insoluble Salt

The author, after explaining the methods hitherto proposed for purifying the phosphoric acid of bone earth, and pointing out their inconveniences, mentioned that the chief difficulty was the separation of the magnesia always present in bone earth. The lime, it has been for some time known, may be entirely removed by means of sulphuric acid. In repeating the process of Liebig, which did not succeed in his hands, and which requires the use of alcohol, he found that, after the separation of the lime, there is obtained, by evaporation and heating, a clear and colourless glass, containing all the magnesia: that this glass dissolved completely by boiling in water; but that the solution, if again evaporated and heated to 600° for a quarter of an hour in a platinum capsule, became turbid, and deposited the whole magnesia as an insoluble salt. When water was added, so as to dissolve the phosphoric acid, and the insoluble salt separated by the filter, the filtered liquid was found absolutely free from magnesia, and was a solution of pure phosphoric acid.

scholarly journals Lung function, pharmacokinetics, and tolerability of inhaled indacaterol maleate and acetate in asthma patients

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
David Miller ◽  
Soniya Vaidya ◽  
Juergen Jauernig ◽  
Brian Ethell ◽  
Kristina Wagner ◽  
...  
Keyword(s):  
Lung Function ◽  
Systemic Exposure ◽  
Forced Expiratory Volume ◽  
Fixed Dose ◽  
Chronic Obstructive ◽  
Electronic Diary ◽  
Double Blind ◽  
Once Daily ◽  
Long Acting ◽  
Salt Forms

Abstract Background Indacaterol maleate delivered with the Breezhaler® inhalation device is a long-acting β2-agonist approved for chronic obstructive pulmonary disease. In the development of a once daily, inhaled fixed dose combination (FDC) of indacaterol, glycopyrronium bromide (a long-acting muscarinic antagonist), and mometasone furoate (an inhaled corticosteroid [ICS]) for the treatment of patients with asthma, the acetate salt of indacaterol is used instead of the maleate salt. Here, we investigated the lung function, pharmacokinetics (PK) and safety of indacaterol maleate 150 μg once daily (o.d.) and indacaterol acetate 150 μg o.d. in comparison with placebo. Methods This was a randomised, double-blind, three-period crossover study (ClinicalTrials.gov identifier, NCT03257995) in patients with asthma on background ICS therapy. Patients with percent predicted pre-bronchodilator forced expiratory volume per second (FEV1) ≥50% and ≤ 90% were included in the study. Patients received indacaterol maleate 150 μg o.d., indacaterol acetate 150 μg o.d., or placebo on top of stable background ICS in randomised sequence. Trough FEV1 was assessed after 14 days of treatment. PK of indacaterol salts were assessed at steady state after 14 days of treatment; peak expiratory flow (PEF) rate and rescue medication use were collected with a combined PEF-meter/electronic diary throughout the study. Results Of the 54 adult patients (median age of 48 years), 51 patients completed the study. Both indacaterol salts demonstrated statistically significant improvements in trough FEV1 of 186 mL (maleate) and 146 mL (acetate) compared with placebo (both P < 0.001). FEV1 AUC0-4h improved by 248 mL (maleate) and 245 mL (acetate), and PEF by 33 L/min (maleate) and 30.8 L/min (acetate) versus placebo. Systemic exposure of indacaterol (AUC0-24h,ss and Cmax,ss on Day 14) was comparable after administration of both salt forms. Both salt forms demonstrated a good safety profile and were well tolerated, with a difference in the reporting frequency of AEs of coughing (maleate, 23.5%; acetate, 0%). Conclusions In patients with asthma, indacaterol maleate and acetate elicited comparable and significant improvements in lung function compared with placebo and achieved comparable systemic exposure. Both indacaterol salts were safe and well tolerated. Trial registration ClinicalTrials.gov NCT03257995 June 06, 2017

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