Salt form of drug

The relative size of the counterion plays an important role in solubility. The following principles were outlined by Amis (1983) for 1 1 salts, which include most salt forms of drugs ... 

Bighley, L. D., S. M. Berge, and D. C. Monkhouse. 1995. Salt forms of drugs and absorptEmc olopedia... 

Exothermic Crystallization Precipitation Solidification Adsorption Solvent vapor induced crystallization of amorphous excipients Formation of salt forms of drug substances Melt granulation with semisolid excipients Solvent vapor sorption by drug substances... 

A number of salt forms of drugs have surfactant properties, which may contribute to their high solubility, membrane transport, and drug absorption. Examples include diclofenac, A-(2-hydroxyethyl)pyr-rolidone (DHEP), and DDNL used in topical pro-ducts.[ ° l... 

Salt formation may be key for the efficient purification of ionizable compounds. Various salts can display different solubilities and tendencies to crystallize and might possess physicochemical differences that can be exploited for convenient processing on scale. Salt forms of drug candidates are selected for desired stability, bioavailability, and formulation characteristics (Chapter 12). A few trends for salt selection are shown in Table 11.4. 

The stability of the salt could also be an important issue, and depending on the pKa, many properties can change, including indirectly related physical characteristics, such as volatility (e.g., hydrochloride salts are often more volatile than sulfate salts). Discoloration of the salt form of drugs is also prominent for some specific forms, as the oxidation reactions (often accompanied by hydrolysis) are a result of factors, such as affinity for moisture, surface hydrophobicity, and so on. Hydrolysis of a salt back to the free base may also take place if the pK of the base is sufficiently weak. 

Many other examples can be found in the literature that demonstrate the applicability of examining a number of salts to obtain the necessary properties needed for development and marketing of the drug substance. Excellent reviews on salts (9,12) discuss many of the issues involved in targeting salt forms of drug substances. 

Thus, as the pH increases, the dissolution rate of a weak base decreases. Referring to Table 2, we can see that, for the weak acid tolbutamide, the dissolution rate increases as pH is increased, as predicted by Eq. (3). Additionally, for the weak base tetracycline, as predicted by Eq. (4), the dissolution rate decreases as pH is increased. Thus far, the more rapid dissolution of the salt forms of these drugs and the direction of change of the dissolution rate with pH have been accounted for with Eqs. (1) to (4). However, there are six possible dissolution rate... 

Numerous other examples of the use of solubility to control the delivery profile of drugs from the elementary osmotic pump can be found in the literature, especially the patent literature [35-40], These systems apply to drugs of moderate to high aqueous solubility where either the excipient or the salt form of the drug was used to control the drug solubility within the core formulation. 

Drugs can cause a wide variety of other autoimmune reactions. One example is myasthenia gravis, which is characterized by muscle weakness and is mediated by antibodies against the acetylcholine receptor at the neuromuscular junction. It has been reported in association with penicillamine [66], gold salts [67], and procainamide [68]. Another form of drug-induced autoimmunity is polymyositis, which is an autoimmune disease... 

It is common practice in pharmaceutical industry to generate salt forms of a drug substance to improve solid-state properties and solubility. CE has proven its ability to analyze reliably organic acids (direct, indirect detection) and alkaline/earth alkaline metals and basic amino acids. For basic drugs, a non-toxic organic acid or inorganic acid is chosen as counterion. Acidic drug substances will usually be deprotonated by alkaline and earth alkaline... 

The active ingredients in MDIs are usually water-soluble and chlorofluorocarbon- or hydrofluorocarbon-insoluble. Some CFC and HFA formulations use ethanol as a suspending agent by using an ethanol-insoluble salt form of the drug. Since the vehicle in MDIs must be propellant-based, a product with the drug suspended in the propellant may be the most stable dosage form. 

The salt form of the polymer may also play a role in determining the performance of the formulation. Kane et al. [32] found that cellulose acetate phthalate was more effective than cellulose acetate trimellitate in controlling the dissolution of sulfothiazole-sodium tablets with cellulose acetate. The enteric properties of hydroxypropylmethylcellulose phthalate (HPMCP) were found to depend on the solubility of the drug that was coated. 

Many commercially available and investigational drugs are anionic or cationic salt forms of weak acids or weak bases (undissociated). Their properties (solubility, partition coefficient, bioavailability, etc.) are strongly dependent upon the degree of ionization, the pH of the solution, and other constituents in the solutions of the drugs. In this chapter, ionic equilibrium calculations will be demonstrated in order to facilitate study of their properties. 

Section 2.2.1 discussed the ionic equilibria of undissociated acids or bases. The majority of commercial (or investigational) drugs are the salt forms of weak acids or weak bases. Let us examine the ionic equilibria when the salt formed between a weak base and a strong acid (HBX) is placed into solution. When the salt is placed into a solution, it completely dissociates into HB+ and X. The ionic weak acid (HB+) is further hydrolyzed as ... 

Particle Size of Raw Materials in Solution Particle size is affected by the breaking process of the particle, crystal form, and/or salt form of the drug. The particle size can affect the rate of dissolution of raw materials in the manufacturing process. Raw materials of a finer particle size may dissolve faster because they have a larger surface area in contact with the solvent than those of a larger particle size when the product is compounded [6], Mixing faster causes the particle to break down and dissolve more quickly. In addition, hydrated particles are less soluble than their anhydrous partners [37],... 

A comparison of Equations (6)-(8) shows important similarities they depend on the solubility of the drug, the area of the device, and the thickness of the membrane. This means that an increased solubility, larger area of the membrane, and thinner membranes will facilitate the drug release rate. This can be exemplified by a study by Ragnarsson and Johansson [11], who showed that, for different salt forms of metoprolol, an increased solubility also increased the drug release rate, which was predicted from the equations. Furthermore, Equations (6)-(8) show constant and time-independent release rates. This constant amount of released drug will be a biopharmaceutical benefit since it theoretically makes it possible to achieve a constant concentration of the drug in the blood plasma. 

This is carried out in order to form the hydrochloride salt form of the drug. This is because that in this system the separation process is based upon, among other mechanisms, an ion-exchange process. 

Having collected the data, a calibration curve should be plotted. Since amphetamine is frequently synthesized in dirty apparatus in clandestine laboratories, it may not be possible to determine which salt form of the drug is present. The standard is generally supplied as the sulfate form, of the general formula (amphetamine)2 sulfate. This means that for every gram of amphetamine sulfate, 73% will be present as the amphetamine free base. The calibration curve should be plotted as (UV detector) response against concentration of amphetamine free base. Exemplar data are presented in Table 2.6 and Figure 2.7. 

The base reacts with the sulfuric acid that is produced when the salt form of the drug dissociates in aqueous solution. The free base form of the drug which is subsequently generated is not freely soluble in water, and thus will precipitate. 

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