Parenteral formulations stability

Studies of polymorphs in recent years have pointed out the effects of polymorphism on solubility and, more specifically, on dissolution rates. The aspect of polymorphism that is of particular concern to the parenteral formulator is physical stability of the product [8]. Substances that form polymorphs must be evaluated so that the form used is stable in a particular solvent system. Physical stresses that occur during suspension manufacture may also give rise to changes in crystal form [9]. 

Y. J. Wang and M. A. Hanson, Parenteral formulations of proteins and peptides Stability and stabilizers. 

The antimykotie amphotericine is eneapsulated in liposomes and marketed as Am-Bisome" against severe systemic mycosis. The liposomal encapsulation reduces the toxicity of amphotericine while increasing the half-life of the drug and plasma level peaks [31], For stability reasons, the parenteral formulation is a lyophilized powder whieh has to be reeonstituted by adding the solvent just before administration. 

One must also remember that precipitation can occur on dilution with other intraverarixili Investigation of dilution in common parenteral vehicles, for example, normal saline, 5% dextrose solution, or likely coadminstered drug products should be conducted for solubility and stability purposes before recommending such procedures. Phlebitis, hemolysis, and pain on injection are also issues for parenteral formulations containing cosolvents. 

Lin SL. Parenteral formulations. I. Comparison of accelerated stability data with shelf-life studies. Bull Parenter Drug Assoc 1969 23 269-288. 

Most peptides and proteins are currently formulated as parenteral formulations because of their poor oral bioavailability. Nevertheless, oral delivery of peptides and proteins would be the preferred route of administration if bioavailability issues could be overcome, as it offers the advantages of convenient, pain-free administration. Although various factors such as permeability, chemical and metabolic stability and gastrointestinal transit time can affect the rate and extent of absorption of orally administered peptides and proteins, molecular size is generally considered the ultimate obstacle [36]. 

Nassar MN, Nesarikar VN, Lozano R, Parker WL, Yande P, Palaniswamy V, Xu W, Khaselev N. 2004. Influence of formaldehyde impurity in polysorbate 80 and PEG-300 on the stability of a parenteral formulation of BMS-204352 identification and control of the degradation. Product Pharm. Dev. 9 189-195. 

Nonionic surfactants consist of a -(CH2CH20)n0H or -OH as the hydrophilic group and exhibit a variety of hydrophile-lipophile balances (HLB) which stabilize O/W or W/O emulsions. Unlike anionic and cationic surfactants, nonionic surfactants are useful for oral and parenteral formulations because of their low irritation and toxicity. Based on their neutral nature, they are much less sensitive to changes in the pH of the medium and the presence of electrolytes. The best use of nonionic surfactants is to produce an equally balanced HLB of two nonionic surfactants one... 

As mentioned previously, the stability of parenteral formulations is often established through the use of buffer systems, and Table 2 contains a partial listing of such systems. ... 

The hydrolysis kinetics of vidarabine-5 -phosphate were studied at a variety of pH values that enabled the compound to exist as its protonated, neutral, and monoionized form. It was found that the hydrolysis reaction followed first-order kinetics at the five pH conditions tested, and that the buffer system used did not influence the reaction rates. The pH-rate profile suggested that even though the compound was most stabile over pH 9.0 to 9.5, the stability at pH 7.4 (i.e., physiological pH) was more than adequate for development of a parenteral formulation. 

Buffers can also be provided in parenteral formulations to ensure the required pH needed for solubility and/or stability considerations. Other excipients included in parenteral products are preservatives (e.g., benzyl alcohol, p-hydroxybenzoate esters, and phenol), antioxidants (e.g., ascorbic acid, sodium bisulfite, sodium metabisulfite, cysteine, and butyl hydroxy anisole), surfactants (e.g., polyoxyethylene sorbitan monooleate), and emulsifying agents (e.g., polysorbates). An inert gas (such as nitrogen) can also be used to enhance drug stability. Stability and solubility can also be enhanced by the addition of complexation and chelating agents such as the ethylenediaminetetraacetic acid salts. For a more detailed list of approved excipients in parenteral products, the reader should consult the monographs within the USP. 

Several new excipients are being evaluated in order to increase the solubility or improve the stability of parenteral drugs. Cyclodextrins have been tried for the above reasons. Currently, there are two FDA approved parenteral products that have utilized a and y-cyclodextrins. p-cyclodextrin is unsuitable for parenteral administration because it causes necrosis of the proximal kidney tubules upon IV and subcutaneous administration. Hydroxypropyl p-cyclodextrin (HPpCD) and sulfobutylether p-cyclodextrin (SBE-7-p-CD) have shown the most promise. Captisol is the trade name of SBE-7-p-CD and is anionic. Currently, two CaptisoF based small molecule IV and IM drug formulations are in Phase III clinical trials in the United States. One parenteral formulation that utilizes HPpCD (Cavitron ) is in Phase II/III clinical trials, and another (Sporanox) has been approved by... 

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. 

Additionally, sodium bicarbonate is used in solutions as a buffering agent for erythromycin, lidocaine, local anesthetic solutions, and total parenteral nutrition (TPN) solutions. In some parenteral formulations, e.g., niacin, sodium bicarbonate is used to produce a sodium salt of the active ingredient that has enhanced solubility. Sodium bicarbonate has also been used as a freeze-drying stabilizer and in toothpastes. 

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. 

Equally important in screening initial preformulations is the selection of a rubber stopper compatible with protein solutions. The variety of composition of mbber stoppers in parenteral formulations of biopharmaceuticals requires studies on compatibility with proteins, involving chemical extractants from the rubber composition into the protein solution over periods of stability at varying temperatures. We must also consider particle shedding from the stoppers into the protein solution, adsorption, absorption, permeation through the... 

Whilst co-solvents can increase the solubility of compounds, on occasion they can have a detrimental effect on their stability. For example, a parenteral formulation of the novel antitumour agent carzelsin (U80,244), using a polyethylene glygol 400 (PEG 400)/absolute ethanol/polysorbate 80 (PET) formulation (ratio 6 3 1, v/v/v), has been reported (Jonkman-De Vries et al. 1995). Whilst this formulation effectively increased the solubility of the compound, this work showed that interbatch variation of PEG 400 could affect the stability of the drug through pH effects. 

In almost all studies, a reference formulation is needed, either as a comparator for assessment of relative performance compared to the test formulation, or as a simple vehicle, to characterise the drug substance pharmacokinetics. If the aim is to investigate the influence of certain formulations on the rate and extent of absorption, which is the case in early development or IVIVC studies, an oral solution of the drug is the first choice as a reference formulation. Stability of the solution, regarding drug compound degradation and precipitation, is an important factor to verify before study start. Inclusion of a parenteral reference formulation, if feasible, provides additional information, as will be further discussed below. 

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