A number of drugs are unstable in an aqueous environment, even when exposed for a short duration, thus requiring packaging, storage, and shipping in a powder or lyophilized state to keep the product stable during its shelf life. Used for parenteral administration, these drugs are commonly known as powder for injection (PI), powder for reconstitution, dry powder injection, or powder for constitution. USP 29–NF 24 describes more than 100 drugs available as dry powder for injection (1).
Typically, PI drugs are supplied in glass vials with rubber plugs and are mixed or reconstituted with a diluent (usually 5% dextrose solution, normal saline, bacteriostatic water, or sterile water for injection) before administration. An incompletely dissolved product can be hazardous to the patient, thereby making reconstitution a critical performance parameter for these products (1). USP defines the completeness of the reconstitution procedure as the state in which the solid dissolves completely; leaving no visible residue as undissolved matter or the constituted solution is not significantly less clear than an equal volume of the diluent or purified water present in a similar vessel and examined similarly (1). The International Conference on Harmonization (ICH) Q6A guideline on drug specifications recommends that "for dry products for injection, acceptance criteria for redispersibility or reconstitution time should be provided and the procedure for resuspension or reconstitution (mechanical or manual) should be indicated. Time required to achieve resuspension or reconstitution by the indicated procedure should be clearly defined" (2).
Variability in the reconstitution time of a product from the same or different manufacturers can seriously affect patient safety. The mention of a specific reconstitution time in the product literature or label could ensure a reproducible performance of the product in terms of complete reconstitution. Few USP monographs of PIs specify the reconstitution time. For example, the monograph for amifostine sulfate, an anticancer drug, specifies the reconstitution time in 0.9% w/v sodium chloride solution to be not more than 45 s (3). Few PI products available in the market mention the time required for their reconstitution either on the label or in the literature supplied with the product. For instance, haemosolvate factor VIII, a glycoprotein necessary for blood clotting and hemostasis, specifies the reconstitution time to be not greater than 30 min. The long reconstitution time required for this product is because reconstitution must be carried out by gentle swirling to avoid foaming and gel formation in the product (4). However, for some drugs such as decitabine hydrochloride, a prolonged reconstitution time might be detrimental to drug stability (5). Therefore, special inputs from formulation scientists are required to optimize the reconstitution time during the development of these dosage forms.
Intrinsic parameters affecting reconstitution time
Intrinsic parameters are inherent to an active pharmaceutical ingredient (API) or a formulation and include the molecular-, particle-, and bulk-level solid-state properties of the API. Any added excipients also influence the inherent reconstitution properties of the product.
Particle-size distribution. Powder dissolution is a kinetic phenomenon that depends primarily on the surface area exposed to the solvent, which in turn is a function of particle size. Particle size, therefore, influences reconstitution time. Coarser particles lower the dissolution rate because of their lower specific surface area in accordance with the Noyes Whitney equation (6). Conversely, very fine particles agglomerate because they are more cohesive (7) and therefore show longer wetting time, resulting in prolonged reconstitution (8). Therefore, particle size must be optimized and controlled to obtain short and reproducible reconstitution times. Particle shape and size affect the closeness of the powder packing, which in turn affects the penetration of water into interstitial spaces of the powder bed (9). Water penetration promotes wetting of each particle that is required before dissolution. Small particle size and symmetrical shape enhance close packing of particles, thus preventing the required penetration of water. Larger particles are usually more irregular in shape and therefore provide more space in the interstices for wetting.