Within a particular method, reconstitution time is further dependent on several variables, including shaking frequency, height of stroke, inclination of the shaking axis, and the dimensions of the mockups. Thiermann et al. studied the reconstitution of HI 6 dichloride, a broad-spectrum cholinesterase reactivator, and observed that horizontal shaking reduced the frequency required for reconstitution (57). Shaking intensities may vary significantly among patients, healthy subjects, doctors, and nurses resulting in differences in reconstitution time (57). Freeze-dried or lyophilized protein drugs need unique reconstitution procedures to avoid excessive stress that might lead to foaming. Foaming causes physical instability of proteins such as denaturation, surface adsorption, aggregation, and precipitation, which might evoke undesired immune response in a patient. It is, therefore, recommended to reconstitute these drugs by either rolling them between palms or swirling thrm despite higher reconstitution times observed with these methods (58).

Storage conditions and storage time. A change in reconstitution time may be observed during storage of a PI. Common reasons include cohesion, crystal growth, and/or moisture sorption, which promote lump formation. Cohesional forces increase with reduced distance between the particles and become prominent in the powder cake, which is usually a result of vibrations experienced by the product during transit or storage. Stresses during storage might induce crystal-form transformations and ultimately alter the reconstitution time (59).

Treatment of glass vial. Glass vials are sometimes coated internally with a silicone fluid to produce a hydrophobic surface. This operation is usually performed to avoid sticking or adherence of drug to the glass vial, thereby ensuring better reconstitutability (60). However, use of organic cosolvents as diluent must be avoided with siliconized glass vials or stoppers because organic cosolvents can solubilize or extract silicone oil from the package component. The extracted silicone oil can impede the wetting of the affected portions of the cake, resulting in incomplete reconstitution (48).

Temperature of diluent. The temperature of the diluent influences the reconstitution time. A significant reduction in reconstitution time was observed using diluent prewarmed to 41 °C for dantrolene (62). Although a warmed diluent would speed up the reconstitution of almost any powdered substance, it might adversely affect the drug stability, which may necessitate the evaluation of the effect of temperature by conducting appropriate stability studies (62). Reconstitution of lyophilized amifostine powder (500 mg) with 2.9 mL sodium chloride solution or sterile water for injection at 20–25 °C resulted in complete dissolution within minutes. Reconstitution with smaller volumes (2.0 or 2.5 mL), although feasible, required more time and/or a warmer temperature (63). Dissolution of amifostine for subcutaneous injection was thus proved to be volume and temperature dependent (63). Mitchell et al. showed that dantrolene solubility increases linearly with increasing temperature between 20 and 40 °C (64). However, a temperature higher than 40 °C is not recommended because it could cause red blood cell lysis and local tissue burns (64, 65).

Conclusion

Reconstitution, a pharmaceutical prerequisite for powder for injection, has direct implications on patient safety, making it a critical parameter to evaluate powder for injection formulations. Numerous intrinsic and extrinsic parameters affect the time and reproducibility of reconstitution of powders. Identification and control of these parameters during product development and quality control can reduce batch-to-batch variability in reconstitution time and provide confidence among the end users, thereby making the powder for injection formulation an attractive and safe alternative for moisture-sensitive drugs. A short and reproducible reconstitution time will also save the precious time and labor of caregivers while dealing in emergency situations, ensuring a more effective critical care during compromised clinical situations.

Pradip Hiwale, Aeshna Amin, and Lokesh Kumar are students and Arvind K. Bansal, PhD,* is an associate professor in the Department of Pharmaceutical Technology (Formulations) at the National Institute of Pharmaceutical Education and Research, Sector 67, Phase X, SAS Nagar, Punjab 160 062, India, tel. 91 172 2214682-87, fax 91 172 2214692, akbansal@niper.ac.in

*To whom all correspondence should be addressed.

Submitted: June 27, 2007. Accepted: Aug. 2, 2007.