Parenteral formulations tonicity

The user enters all known data on the solubility (aqueous and non-aqueous), stability in specified solutions, compatibility, pAia, and molecular properties of the active ingredient (molecular weight, log/, etc.). As with the system for tablet formulation, the data may be numerical or symbolic. All relevant properties of additives used in parenteral formulation (e.g., buffers, antioxidants, chelating agents, antimicrobials, and tonicity adjusters) are present in the knowledge base. 

The four colligative properties that are of importance are 1) the vapor pressure lowering 2) the elevation of boiling point 3) the freezing-point depression and 4) the osmotic pressure. An attempt is made below to describe qualitatively and quantitatively each colligative property of solutions, with an emphasis on their interrelationship and their application later in measurement and adjustment of the tonicity of solutions, with particular reference to parenteral formulations. Although theoretical derivations based on thermodynamics can be used to show how each of the colligative properties of solution arises and relate to each other, textbooks on physical chemistry for theoretical derivations are recommended. 

It has been also observed that hypertonic and hypotonic salt solutions tend to irritate sensitive tissue and cause pain when applied to mucous membranes of the eye, ear, and nose, etc., whereas isotonic solution causes no tissue irritation when it comes in contact with the tissue. Obviously, the tonicity of formulations that come in to direct contact with blood, muscle, eye, nose, and delicate tissues is critical. Therefore, the issue of tonicity is important in small- and large-volume injectables, ophthalmic products, and products intended for tissue irrigation. The degree of tissue irritation or hemolysis or crenation observed depends on the degree of deviation from isotonicity, the volume injected, the speed of injection, the concentration of the solutes in the injection, and the nature of the membrane. The parenteral and ophthalmic formulations are therefore adjusted to isotonicity if possible. 

An increase of the ionic strength of aqueous solutions of glutaminyl and asparaginyl pen-tapeptides has been reported to result in an increased rate of deamidation. Similar results have been noted in an earlier study on cytochrome c, although a lack of effect of ionic strength on stability was observed in a series of pentapeptides Val-Ser-Asn-X-Val and Val-X-Asn-Ser-Val, where X is an amino acid. The ionic strengths of most parenteral formulations of proteins in which sodium chloride is used to adjust the tonicity are sufficiently low that increased deamidation rates resulting from electrolyte addition will not be a major problem. 

Liquid formulations for parenteral use require preparation methods and composition that make the formulation stable and sterile. Other requirements for parenteral formulations are given by the European Pharmacopoeia such as tonicity, efficacy of the antimicrobial... 

Parenteral formulations often contain excipients considered to be chemically stable and inert however, all excipients in a formulation may influence the photochemical stability of the product. Dextrose and sodium chloride are used to adjust tonicity in the majority of parenteral formulations. Sodium chloride can affect photochemical processes by influencing solvation of the photoreactive molecules (see Section 14.2.3). The ionic strength is reported to affect the photochemical decomposition rate of minoxidil until a saturation level is reached (Chinnian and Asker, 1996). The photostability of L-ascorbic acid (vitamin C) in aqueous solution is enhanced in the presence of dextrose, probably caused by the scavenging effect of the excipient on hydroxyl radicals mediated by the photolysis of ascorbic acid sucrose, sorbitol, and mannitol have the same effect (Ho et al., 1994). Monosaccharides (dextrose, glucose, maltose, and lactose), disaccharides (sucrose and trehalose), and polyhydric alcohols (inositol, mannitol, and sorbitol) are examples of commonly used lyo-additives in parenterals. These excipients may also affect photochemical stability of the products after reconstitution. 

Several good surfactants in terms of solubility, compatibility, and toxicity can be selected for prototype formulation development. In general, one surfactant can be used as the primary solubilizer in a prototype formulation. Functional excipients, such as antioxidants, tonicity agents for parenteral products and sweeteners, and taste masking agents for oral products, may be added to the prototyp formulation. 

Parenteral solutions should be of approximately the same tonicity as blood semm the amount of adjusting substance which must be added to a formulation to achieve isotonicity can be calculated using the... 

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