The Influence of Hydro-Alcoholic Media on Drug Release - Pharmaceutical Technology

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The Influence of Hydro-Alcoholic Media on Drug Release
The authors investigate the influence of hydro-alcoholic media on hydration and drug release from polyethylene oxide extended-release matrices.


Pharmaceutical Technology
Volume 35, Issue 7, pp. 50-58

Results and discussion


Figure 1: Gliclazide 30 mg release profile from polyethylene oxide extended-release matrices in different media containing 0, 5 or 40% w/v ethanol (n = 3). (FIGURE IS COURTESY OF THE AUTHOR)
The effect of hydro-alcoholic media on drug release from PEO ER matrices. Robust PEO ER matrices with strength values of 2.32 MPa (13.0 0.2 kp) for gliclazide and 0.70 MPa (14.0 0.5 kp) for metformin HCl were produced. Reproducible drug release profiles were obtained for both formulations in all tested media. No dose dumping from the PEO matrices was observed even after 12-h exposure to the hydro-alcoholic media.


Table IV: f2 values for drug release profiles from polyethylene oxide matrices in hydro-alcoholic media compared with non-exposure to ethanol solutions.
Figure 1 and Table IV show that gliclazide release was not significantly affected by either 1- or 12-h exposure to 5% or 40% w/v ethanol solutions. The differences observed in the dissolution profiles can be attributed to the different solubility of the drug in ethanol (see Table III).


Figure 2: Metformin HCl 500 mg release profile from PEO ER matrices in different media containing 0, 5 or 40% w/v ethanol (n = 3). (FIGURE IS COURTESY OF THE AUTHOR)
Metformin HCl release from PEO ER matrices in hydro-alcoholic media was similar to the dissolution results in water in all the tests (f 2 > 50), with the exception of the 12-h exposure to 40% w/v ethanol (f 2 = 42), where drug release was significantly slower (see Figure 2 and Table IV). This result can be explained by a reduction in metformin HCl solubility from 450 mg/mL in water to 295 mg/mL in 40% v/v ethanol (18). However, such extreme conditions (i.e., high concentration of ethanol during a prolonged period of time) are unlikely for in vivo conditions. In the human body, tablets taken with alcohol are unlikely to be exposed to a 40% v/v hydro-alcoholic medium for a 12-h period because of the rapid absorption of ethanol from the gastro-intestinal tract (18, 33). This study did not reveal any effect on dissolution after 1-h exposure of PEO ER tablets to hydro-alcoholic media for either active.

Drug-release variability, in particular with gliclazide, increased when matrices were tested in alcohol. The standard deviation for gliclazide tablets subjected to hydro-alcoholic media increased from 2.3% (no exposure to alcohol) up to 3.6% (exposure to 5% w/v alcohol) and up to 5.6% (exposure to 40% w/v alcohol), respectively (see Figure 1). This result may be due to the influence of ethanol on hydration of the polymer and erosion of the gel structure on the surface of the matrix.


Table V: Values of the kinetic constant (k), diffusion exponent (n) derived from Equation 1, and correlation coefficients (R2) for PEO ER matrices in various media.
The values of the kinetic constant (k), the release exponent (n), and correlation coefficient (R 2) determined from the drug release data are presented in Table V. As gliclazide is practically insoluble in water and slightly soluble in alcohol (see Table III), its release from ER hydrophilic matrices was expected to occur predominantly by gel erosion. This was confirmed by high n values (1.3–1.4) suggesting that erosion was the main mechanism of gliclazide release from PEO matrices in all studied dissolution media.

On the other hand, a combination of diffusion and erosion (n = 0.6-0.7) was observed with metformin HCl (see Table V), which was anticipated due to its high aqueous drug solubility. Metformin HCl solubility changes from freely soluble in water to slightly soluble in alcohol (see Table III), resulting in a greater erosion contribution to the drug release from the tested PEO matrices. This was reflected by an increase in n value from 0.61 in water to 0.63 and to 0.74 in 5 and 40% w/v ethanol solutions, respectively. These findings agree with the Roberts data showing that ethanol affects the kinetics and mechanism of drug release from hydrophilic matrix tablets, but does not result in dose dumping (29).

Because the values of n and k are inversely related, k values changed slightly from 32.96 in water to 33.50 and 24.24 for metformin HCl tablets exposed to 5% and 40% w/v ethanol solutions, respectively. These results imply that the rate of drug release is slightly slower in 40% w/v ethanol solution than in water.

For both formulations, greater erosion contribution to the drug release from the tested matrices was observed in ethanol solutions compared with aqueous media. The results of this study identified similar trends to the previously published data for HPMC ER matrix systems (18). This finding is interesting in light of gastrointestinal tract motility. According to Bode and Bode, alcohol may interfere with the activity of the muscles surrounding the stomach and the small intestine and thus alter the transit time of food through these organs (48–49). In humans, alcohol's effect on gastric motility depends on the alcohol concentration and accompanying meals. In general, beverages with alcohol concentrations above 15% appear to inhibit gastric motility and thus delay the emptying of the stomach. In the small intestine, alcohol decreases the muscle movements that help retain the food for further digestion (i.e., the impeding wave motility). However, alcohol does not affect the movements that propel food through the intestine (i.e., the propulsive wave motility) in either alcoholics or healthy subjects.


Figure 3: Effect of hydro-alcoholic media containing 0, 25 or 50% w/v ethanol on wet weight of PEO (Polyox 1105, 301 and Coagulant) compacts (n = 3). (FIGURE IS COURTESY OF THE AUTHOR)
It is also important to take into account the solubility of additional excipients (e.g., fillers, bulking agents, and surfactants) used in the formulation. The most popular fillers used in hydrophilic matrix systems can be ranked in ascending order according to their solubility in ethanol: MCC and dicalcium phosphate dehydrate, pregelatinized starch, and lactose (18). Practically insoluble in both water and aqueous alcoholic solutions, MCC was the filler least likely to be affected by the dissolution media choice in this study.


Table VI: Effect of hydro-alcoholic media on wet weight of Polyox compacts (n = 3).
The effect of hydro-alcoholic media on swelling of pure PEO compacts. Mechanically strong compacts (i.e., >21 0.5 kp, > 3.3 MPa) were produced for all three grades of PEO tested in this study. In water and hydro-alcoholic solutions all PEO tablets underwent swelling and gelation without any disruption to the matrix integrity. A similar progressive weight gain by compacts made of various viscosity grades of PEO was observed in water and hydro-alcoholic media (see Figure 3 and Table VI). For high viscosity grades of PEO (e.g., Polyox 301 and Coagulant), a slightly lower swelling and gel formation in the presence of ethanol was recorded. This result can be attributed to a decrease in polymer solubility in alcohol compared with water (see Table III), retarded hydration of the polymer, and the resulting change in gel viscosity (29, 31, 50–51).


Table VII: Effect of various media on relative swelling of Polyox compacts (n = 3).
Table VII shows that the extent of swelling increased with increasing molecular weight (MW) of PEO from 900,000 Da (Polyox 1105) to 4,000,000 Da (Polyox 301). However, no significant difference in compact relative swelling was observed when MW was further increased from 4,000,000 Da (Polyox 301) to 5,000,000 Da (Polyox Coagulant).


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