Preparing pharmacy graduates for traditional and emerging career opportunities.

Educational programs in pharmacy must focus on educating pharmacists of the future who are prepared to serve as competent and confident health care "providers" whose "practice" can occur in any number of current and future settings; and whose expertise is essential to an interprofessional health care team. Graduates must be able to incorporate a scholarly approach to their practice in identifying patient care problems; practicing in an evidence-based manner; and ensuring safe, effective, and appropriate use of medications. It is time for colleges and schools of pharmacy to implement contemporary teaching and assessment strategies that facilitate effective and efficient student learning that is focused at the graduate professional level, to evolve the content around which the curriculum is organized, and clearly articulate the abilities graduates must have to function effectively in the myriad professional roles in which they may find themselves.

General pharmaceutics--the new physical pharmacy.

General Pharmaceutics is proposed as the broad study of the biopharmaceutical and physical chemical properties of each potential drug substance. When the first quality bulk lot is delivered, usually the first GMP bulk lot, an extensive profiling of the potential drug substance should commence. This profile should include solid-state characterization as well as thorough analyses of solubility, stability, and absorption properties of the drug substance that could affect the development of a viable medicine. As a result of these studies, a number of initial specifications could be developed: the preferred polymorphic or crystalline form identified, the preferred particle size to optimize absorption/development, and an initial biopharmaceutics classification with a dose limit to identify those cases in which the formulation can be expected to improve absorption and exposure. The broad topic of General Pharmaceutics is discussed in this Minireview including many advances in technology in this field as well as the rationale behind the proposed initial specifications.

Discovery of the hemifumarate and (alpha-L-alanyloxy)methyl ether as prodrugs of an antirheumatic oxindole: prodrugs for the enolic OH group.

Ether, ester, and carbonate derivatives of the antirheumatic oxindole 1 were prepared and screened as potential prodrugs of 1. This effort led to the discovery of the (alpha-L-alanyloxy)-methyl ether and hemifumarate derivatives of 1 which deliver the drug efficiently into the circulation of test animals, are stable in the solid state, and possess good stability in solution at low pH as required to ensure gastric stability. Success in achieving acceptable bioavailabilities of 1 across species (rats, dogs, and monkeys) followed the inclusion of ionizable functionality within the promoiety to compensate for masking the polar enolic OH group of the free drug. However, the introduction of ionizable functionality was often associated with decreased stability, as demonstrated by the hemisuccinate, hemiadipate, hemisuberate, and alpha-amino ester derivatives of 1 which could not be isolated. A clear exception was the hemifumarate derivative of 1 which was not only isolable but actually more stable at neutral pH than the nonionizable ester analogues. The solution and solid state stability of the hemifumarate, together with its activity as a prodrug of 1, suggests that hemifumarate be considered as an alternative to hemisuccinate as a prodrug derivative for alcohols, particularly in situations where solution state stability is an issue.

Comparison of the acid stability of azithromycin and erythromycin A.

In acidic aqueous media, erythromycin A is rapidly degraded via intramolecular dehydration to form erythromycin-6.9-hemiketal and then anhydroerythromycin, both of which possess little antimicrobial activity. Azithromycin, a new azalide antibiotic, has a methyl-substituted nitrogen in place of the carbonyl at the 9a position of the aglycone ring, thus blocking the internal dehydration pathway. As a result, azithromycin decomposition occurs primarily via acid-catalysed hydrolysis of the ether bond to the neutral cladinose sugar. Rate constants and the time for 10% decay (T1/10) were determined for both azithromycin and erythromycin A at pH2 using various levels of acetonitrile cosolvent and constant ionic strength. Semi-log plots of the decay rate constants versus the reciprocal of the solution dielectric constants were used to extrapolate to totally aqueous conditions. In solution at 37 degrees C and pH2 with ionic strength mu = 0.02, azithromycin was degraded with a T1/10 of 20.1 min while erythromycin underwent 10% decay in only 3.7 sec. The activation energy for hydrolysis of the ether bond connecting cladinose to azithromycin was 25.3 kcal/mol while the internal dehydration reaction of erythromycin had an activation energy of 15.6 kcal/mol. A solution stability profile was generated for azithromycin over the pH range of 1.0 to 4.1 at 30 degrees C. Stability was found to improve ten-fold for each unit increase in pH.

Test method for evaluation of loss of prime in metered-dose aerosols.

A new test method is described for assessing the loss of prime in metered-dose aerosols. Two representative metered-dose valve designs and two storage positions were used to assess the utility of this test method at three different sites. Loss of prime, defined as a valve delivery 15% below the mean, was detected in three of the four test configurations. The first significant loss of prime in this study was observed at the two-week time point for valves without drain tanks stored in the upright position. Onset of loss of prime was shown to be dependent on valve design as well as storage position, thus alternate valves or storage conditions should yield different results. This test method appeared to be reproducible over the three test sites, with a slight variation in results attributed to differences in storage conditions and agitation during sample handling. This test method intentionally excluded agitation which is in sharp contrast to the normal "shake well before use" instruction to the patient. Following one priming actuation, all of the valves returned to their mean valve delivery.