Product Development Issues of Powders for Injection

gory of dosage forms for active molecules. Because of their instability in the aqueous environment, PIs cannot be marketed as ready-to-use injectables (1). Instead, they are marketed as dry powders to be reconstituted with a suitable vehicle just before administration. The final form after reconstitution may be either a solution or a suspension (2). Typical molecules in this category include -lactam antibiotics, cephalosporins, and acyclovir. A few ready-to-use infusion products are marketed as frozen solutions in plastic bags for these molecules. However, the low temperature required for their shipment and storage makes these products an unviable option, especially in countries in which a cold chain from manufacturing to the point of consumption is difficult to establish. Depending on their formulation strategy, PIs can be categorized into any of the classes shown in Figure 1. Two strategies can be adopted for the formulation and manufacture of PIs (see Figure 2). The first strategy of lyophilizing (freeze-drying) the primary pack allows the formulation of drugs that are thermolabile or unstable in aqueous solution. However, lyophilization normally yields an amorphous or partially amorphous product, which leads to solid-state instability (3). A more-stable crystalline stage can be obtained by crystallization in aseptic conditions, and it can be maintained by directly filling the sterile dry-powder drug into presterilized vials (see Figure 2, Strategy 2). The dry-filling process also is much more cost effective because it requires less infrastructure as well as a reduced amount of energy and a shorter amount of time to produce a batch (4). These reasons have made dry-filled PIs a popular dosage form. A PI formulation may consist of drug only or drug plus excipient. Table I lists a few examples of formulations containing functional excipients. The dry-powder fill approach involves depositing a drug (plus excipient) into individual vials using suitable filling equipment. The entire process does not involve the addition of an excipient or processing step except when two drugs or a drug and an excipient are mixed. Complexities resulting from the presence of an excipient (e.g., interactions with the active molecule and product performance) are absent in PIs containing only the active drug. Formulations containing a drug and excipients also are relatively simple in terms of number and variety of excipients. For this reason, formulation development scientists tend to underestimate the development process of PIs. This is where the