Piroxicam dissolution

All piroxicam batches were manufactured in compliance with Good Manufacturing Practices, and three formulations having fast, moderate, and slow dissolution were chosen for comparison to a lot of the innovator s product in a human bioavailability study [100]. The resulting pharmacokinetic data provided still another opportunity to examine the effects of formulation variables. To explore the relationship between the in vitro dissolution of piroxicam from these capsules and in vivo absorption, Polli [ 102] used the following previously described [145] deconvolution-based model ... 

Table 6 Apparent Permeability and Dissolution Rates for Piroxicam Capsules...

It is interesting that the in vitro dissolution test (USP) was more sensitive to the piroxicam formulation variables than the biodata. The fast, moderate, and slow products were found bioequivalent to each other and to the lot of innovator product studied [100]. It is possible that either the formulation variables studied did not affect in vivo dissolution and/or the differences were not discernible because of the long biological half-life of piroxicam [146]. 

DA Piscitelli, S Bigora, C Propst, S Goskonda, P Schwartz, L Lesko, L Augsburger, D Young. The impact of formulation and process changes on in vitro dissolution and bioequivalence of piroxicam capsules. Pharm Devel Tech 3(4) 443-452, 1998. 

In solutions saturated (i.e., excess solid present) at some pH, the plot of log Co versus pH for an ionizable molecule is extraordinarily simple in form it is a combination of straight segments, joined at points of discontinuity indicating the boundary between the saturated state and the state of complete dissolution. The pH of these junction points is dependent on the dose used in the calculation, and the maximum value of log Co is always equal to log. Sb in a saturated solution. [26] Figure 2.2 illustrates this idea using ketoprofen as an example of an acid, verapamil as a base, and piroxicam as an ampholyte. In the three cases, the assumed concentrations in the calculation were set to the respective doses [26], For an acid, log Co (dashed curve in Fig. 2.2a) is a horizontal line (log Co = log So) in the saturated solution (at low pH), and decreases with a slope of —1 in the pH domain where the solute is dissolved completely. For a base (Fig. 2.2b) the plot of log Co versus pH is also a horizontal line at high pH in a saturated solution and is a line with a slope of +1 for pH values less than the pH of the onset of precipitation. 

Mooney et al. [70] investigated the effect of pH on the solubility and dissolution of ionizable drugs based on a film model with total component material balances for reactive species, proposed by Olander. McNamara and Amidon [71] developed a convective diffusion model that included the effects of ionization at the solid-liquid surface and irreversible reaction of the dissolved species in the hydrodynamic boundary layer. Jinno et al. [72], and Kasim et al. [73] investigated the combined effects of pH and surfactants on the dissolution of the ionizable, poorly water-soluble BCS Class II weak acid NSAIDs piroxicam and ketoprofen, respectively. 

Prabhu S, Ortega M, Ma C (2005) Novel lipid-based formulations enhancing the in vitro dissolution and permeability characteristics of a poorly water-soluble model drug, piroxicam. Int J Pharm 301 209-216. 

Fernandez M, Margarit MV, Rodriguez IC, Cerezo A. Dissolution kinetics of piroxicam in solid dispersions with polyethylene glycol-4000. Int J Pharm 1993 98 29-35. 

A high degree of sensitivity of in vitro dissolution tests to formulation differences raises questions about the appropriate acceptance criteria—how similar should two in vitro dissolution profiles be to be considered similar The SUPAC-IR introduced to the regulatory decision-making process a metric referred to as f2 [43] for profile comparison. Application of this criterion to the examples cited in this report (e.g., piroxicam formulations) would have resulted in a recommendation for the in vivo bioequivalence study. 

Shangraw, R. F.. and Demarest, D. Survey of current industrial practice in the formulation and manufacture of tablets and capsules. Pharm. Tech. 17(l) 32-44, 1993. USP 24-NF 19. United States Pharmacopoeia Convention, Inc. Rockville. MD, 2000. Piscitelli, D. A.. Bigora, S., Propst, C.. Goskonda, S., Young. D.. et al. Impact of formulation process changes on in vitro dissolution and the bioequivalence of piroxicam capsules. Phaim. Dev. Technol. 3 443 52, 1998. 

Cavallari, C., Abertini, B., Gonzalez-Rodriguez, M., and Rodriguez, L., Improved dissolution behavior of steam-granulated piroxicam, European Journal of Pharmaceutics and Biopharmaceutics, Vol. 54, No. 1, 2002, pp. 65-73. 

The combined effect of pH and surfactants on the dissolution of piroxicam has been reported. " In this system, the dissolution rate and solubility of the drug substance could be well estimated by a simple additive model for the effect of pH and surfactant, where the total dissolved concentration equaled the summation of the amoimt of dissolved non-ionized substance, the amount of dissolved ionized substance, and the amoimt of substance solubilized in the surfactant micelles. It was suggested that the model developed in this work could be useful in establishing an in vitro-in vivo correlation for piroxicam. 

This effect of particle size on dissolution rate of sparingly soluble drug substances has been demonstrated in many instances by the superior dissolution rates observed after size reduction. Examples of compounds studied in such work include methylprednisolone (Higuchi et al., 1963), l-isopropyl-7-methyl-4-phenylquinazolin-2(lH)-one (Kornblum and Hirschorn, 1970), griseofulvin (Ullah and Cadawader, 1971), monophenylbutazone (Habib and Attia, 1985), nitrofurantoin (Eyjolfsson, 1999), and piroxicam (Swanepoel et al., 2000). 

Swanepoel E, Liebenberg W, de Villiers MM, and Dekker TG. Dissolution Properties of Piroxicam Powders and Capsules as a Function of Particle Size and the Agglomeration of Powders. Drug Dev Ind Pharm 2000 26 1067-1076. 

There are numerous examples of medicinal products in which dissolution rate enhancing technologies are applied to increase the bioavailabiUty or absorption rate of an active substance. Cardiac glycosides should be given as micronised particles in a solid oral dosage form because otherwise their dissolution rate and hence their bioavaUability is too low. Piroxicam was shown to be absorbed faster when given as a cyclodextrin complex, which increases the dissolution rate. Similarly, the bioavailabiUty of albendazole as a cyclodextrin complex was increased compared to crystalline non-complexed albendazole, based on the same mechanism. And finally, the bioavailabiUty of amorphous chloramphenicol is higher than that of crystalline chloramphenicol. 

There are abundant examples in the literature that demonstrate the direct relationship between dissolution rate and bioavailability. One such example is that of piroxicam (Figure 7.6), a potent non-steroidal anti-inflammatory drug that was launched in 1981 by Pfizer for multiple conditions such as arthritis (osteoarthritis and rheumatoid arthritis) and spondylitis. It is a zwitterionic drug (p ai = 1S6 and p a2 = 5.46) and is classified as a low solubility and high permeability drug (i.e., class II) based on the Biopharmaceutics Classification System (BCS). In an attempt to improve its bioavailability after oral administration, the authors prepared three different ethanolamine salt forms i.e., mono-, di- and triethanolamine salts). These salt forms were selected based on prior literature precedence where they enhanced the percutaneous absorption of piroxicam.PK studies of the ethanolamine salts revealed that both the exposure (AUC) and the C ax of piroxicam in plasma followed the same trend as the dissolution profile at pH 6.8, which varied in the order mono- > di- > tri-piroxicam. The monoethanolamine salt showed the highest exposure with the relative bioavailability increasing almost 1.9-fold, while the di- and tri- salts were 1.7 times better than piroxicam. The C ax values showed 2.14-, 1.6- and... 

Cavallari C, Abertini B, Gonzalez-Rodriguez ML, Rodriguez L. Improved dissolution behaviour of steam-granulated piroxicam. Eur J Pharm Biopharm 2002 54 65 73. 

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