Drug formulations suspensions

Fig. 6 Solubility effects on drug stability curve A, drug formulated as lOmg/mL solution (q/2 = 1 year) curve B, drug formulated as a suspension with a saturated solubility of 1 mg/mL (ti/2 = 7.3 years). 

LD50 —The dosage level of a drug that is strong enough to cause death in 50 percent of animals tested referred to as 50 percent lethal dose, liquid suspension— A drug formulation in which the active ingredient is carried (suspended), but not dissolved, in a fluid. 

One of the problems faced in formulating suspensions is that finely divided particles are not easily wetted in water. This may be the result of the hydrophobic nature of the drugs and/or entrapped gases (i.e., air). The wetting process is the displacement of one fluid by another from the solid surface. When wetting solids, the entrapped... 

Nebulizers are devices for converting aqueous solutions or micronized suspensions of drag into an aerosol for inhalation, although the drug formulations are, wherever possible, aqueous solutions. Selection of appropriate salts and pH adjustment will usually permit the desired concentration to be achieved. If this is... 

Drug formulations are designed to provide an attractive, stable, and convenient method to use products. Conventional dosage forms may be broadly characterized in order of decreasing dissolution rate as solutions, solid solutions, suspensions, capsules and tablets, coated capsules and tablets, and controlled release formulations. 

It is important to consider the influence of interaction between functional groups of drugs that leads to their habit modification when formulated in suspension dosage form. Proton transfer from the N atom of sulfamethoxazole to the pyrimidine basic N1 atom of trimethoprim has been reported to occur in their equimolar complexes. Bettinetti et al. have reported nucleation of the complex of trimethoprim and sulfa-methoxypyridazine (1 1) to be accelerated by water or wet granulation. Our studies on cotrimoxazole (unpublished results) revealed immediate formation of fine needle-shaped crystals irrespective of the initial shape of sulfamethoxazole and trimethoprim crystals as a result of the interaction between the two drugs in suspension form. Small needles (Fig. 6A) were... 

Bunge, A.L. Release rates from topical formulations containing drugs in suspension. J. Controlled Release 1998, 52, 141-148. 

Because many medications are not available as liquid preparations, there are times when powder papers or suspensions must be prepared. An excellent information source about the preparation of liquid dosage forms for pediatric patients has been published by Nahata and Hippie (Nahata, M. C., Hippie, T. F. Pediatric Drug Formulations, 4th Ed. Harvey Whitney Books Cincinnati, 2000). 

There are two types of MDI formulations suspension formulations, in which microparticulate drug (typically micronized material) is dispersed in... 

MDIs, be they solution or suspension formulations, typically contain a surfactant or dispersing agent. These materials generally need to have some solubility in the propellant blend. Commonly used surfactants include sorbitan trioleate (SPAN 85), oleic acid, and lecithins, at levels between 0.1% and 2.0% wt/wt [40]. These agents are required both to maintain the disperse nature of the drug (in suspension formulations) and to provide lubrication for operation of the metering valves. However, these surfactants have poor solubility in the HFA... 

A dramatic example of the impact of crystal polymorphism on a drug formulation is that of ritonavir (Norvir ), used for the treatment of HIV patients. The problem arose in May of 1998, approximately two years after the launch of the drug, when researchers at the Abbott Laboratories became aware that after 240 production batches it was no longer possible to obtain ritonavir in the crystal form (Form I) approved by the FDA and required for the formulation of Norvir because of the sudden and unexpected appearance of a more stable and much less soluble crystal form (Form II, Fig. 3.3.17). The loss of control over the production process forced Abbott to withdraw the drug from the market for approximately one year until they learned how to replace the solid formulation with a gel capsule suspension with greater problems of stability and bioavailability. Subsequent investigations have led to the discovery of four other crystalline forms of ritonavir [33]. 

The most common way to formulate injections is to dissolve the drug in an aqueous vehicle. Excipients are added to control solubility, osmotic pressure, pH, stability, specific gravity, and preservation. Injections may also be formulated as oily solutions, disperse systems like suspensions and emulsions (aqueous and oily), and liposomal dispersions. Drug formulation is an essential factor in photochemical stability of the drug substance. Excipients or impurities in the formulation can also participate in photochemical reactions, leading to decomposition of the drug substance or the formulation. 

Photochemical stability of suspensions and emulsions is a rather complicated area. The optical properties of a disperse system (transmission of photons through the formulation and spread of optical irradiation) will depend on the size of the particles or droplets in the disperse phase, the fractional relationship between the disperse and homogenous phases, flocculation in the system, and physicochemical properties of the disperse and homogenous phases. The photochemical stability of a drug formulated as an emulsion will partly depend on the photochemical reactivity of the drug in the lipophilic and hydrophilic phases. The distribution of the drug between the two immiscible phases is an essential aspect to consider as part of an evaluation. Influence of the solvent properties on photochemical reactivity is covered in Section 14.2.2. 

Final formulations, like those used for marketed drugs, are generally not used for Phase 1 studies. Formulation development represents expenditure of significant resources, the approaches used may depend on the results of future bioavailability studies, and the success of the drug candidate is still an open question. Therefore, simple formulations are most often used. For orally administered drugs, solutions are ideal as they provide flexibility in dosing and minimize potential absorption or bioavailability problems. Capsules filled with neat drug or suspensions can be employed when solutions are not feasible. 

A well-formulated suspension is second to a solution in efficiency of absorption. Dissolution is the rate-limited factor in absorption of a drug from a suspension. However, drug dissolution from a suspension can be rapid if very fine or micronized powders are used. (These have a larger surface area or specific surface.)... 

Drugs formulated in tablet and capsule dosage forms may not achieve the state of dispersion in the G1 tract that is attainable with a finely subdivided, well-formulated suspension (Fig. 9.2). 

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