Changes in Drug Dissolution from Tablets and Capsules

Dissolution (or release) of a drug substance from a dosage form, such as a tablet or a capsule, is a very important characteristic. Dissolution characteristics have been known to change upon storage. For example, the dissolution rate of carbamazepine tablets decreased markedly when they were stored at room temperature and 100% RH for a period as short as 6 days (Fig. 163).670 Such dramatic changes in dissolution rate may alter the bioavailability of the drug. However, changes in in vitro dissolution behavior do not necessarily mean that changes in bioavailability will occur. Only in those cases in which dissolution limits bioavailability or in which in vitro dissolution reasonably mimics what happens in vivo is there likely to be a correlation. Although the in vitro dissolution rate of soft gelatin capsules containing digoxin and polyethylene glycol 400 decreased during storage, no significant changes in bioavailability were observed.671 Similarly, a change in the in vitro dissolution rate of etodolac capsules during storage was not reflected in a change in bioavailability.672 However, a nitrofurantoin capsule formulation exhibited a decrease in in vitro dissolution rate and in in vivo absorption rate upon storage.673

4.2.2.1 Effect of Formulation on Changes in Dissolution

The stability of the dissolution characteristics of dosage forms during storage can be affected by formulation components and processing. A phenobarbital tablet containing tablet 1 tablet 2 tablet 3

tablet 1 tablet 2 tablet 3

Figure 163. Changes in dissolution rate of carbamazepine tablets during storage. Before storage; A, after 6-day storage at 100% RH; V, i dried at 85°C after 6-day storage at 100% RH. (Reproduced from Ref. 670 with permission.)

Figure 163. Changes in dissolution rate of carbamazepine tablets during storage. Before storage; A, after 6-day storage at 100% RH; V, i dried at 85°C after 6-day storage at 100% RH. (Reproduced from Ref. 670 with permission.)

gelatin as a binder exhibited a marked decrease in dissolution rate during storage at 98% RH.674 The dissolution rate of hydrochlorothiazide tablets containing acacia increased during storage at high temperatures.675 A decrease in dissolution rate during storage was also observed with a hydrochlorothiazide bead formulation containing sodium starch glyco-late,676 whereas the dissolution rate of nitrofurantoin capsules decreased during storage at high humidity as the content of carbomer increased, leading to a decrease in bioavailability as shown in Fig. 164.677 This was consistent with gelation of the carbomer during storage.

Alginic acid, a tablet disintegrant, exhibited a decrease in swelling force generation after storage under a variety of conditions, indicating the possibility of decreased tablet dissolution (Fig. 165).678 Changes in the rate of dissolution of phenytoin sodium capsules after storage depended on the excipients used; for example, dissolution rate increased with time when calcium sulfate was added but decreased with time when lactose was added.679 Decreased dissolution rate during storage at high humidity has been reported for theophylline pellets and prednisone tablets containing microcrystalline cellulose.680 681

As excipients affect the dissolution characteristics of dosage forms over time, the water content of dosage forms can also affect stability. Higher water content generally causes a larger change in dissolution behavior.666 680 Storage of calcium 4-aminositlicylate tablets at high humidity prolonged the disintegration time and decreased the dissolution rate as shown in Fig. 166.682 Even though the decrease in dissolution was correlated with an increase in water content, the mechanism for this change was not clear. A tablet containing polyvinylpyrroli-done as a disintegrant exhibited a larger change in drug release when stored at 23 °C compared to 65°C, suggesting that water evaporation at higher temperatures leads to stabilization of drug release characteristics.683 It has been reported for both prednisone and erythromycin tablets that moisture-permeable packaging is likely to change the drug release from the tablets.684 685

Figure 164. Changes in nitrofurantoin excretion rate from nitrofurantoin capsules containing different amounts of carbomer and stored under different conditions. A, Before storage; formulation containing less carbomer after I-year storage at 40°C and 30% RH; formulation containing more carbomer after 1-year storage at 40°C and 60% RH. (Reproduced from Ref. 677 with permission.)

Figure 164. Changes in nitrofurantoin excretion rate from nitrofurantoin capsules containing different amounts of carbomer and stored under different conditions. A, Before storage; formulation containing less carbomer after I-year storage at 40°C and 30% RH; formulation containing more carbomer after 1-year storage at 40°C and 60% RH. (Reproduced from Ref. 677 with permission.)

time (min)

Figure 165. Changes in the swelling force of alginic acid after one-year storage under a variety of conditions. O, Before storage. Storage conditions: +, 25°C; x, 30°C; O, 30°C and 75% RH; A, 40°C;O, 50°C. (Reproduced from Ref. 678 with permission.)

time (min)

Figure 165. Changes in the swelling force of alginic acid after one-year storage under a variety of conditions. O, Before storage. Storage conditions: +, 25°C; x, 30°C; O, 30°C and 75% RH; A, 40°C;O, 50°C. (Reproduced from Ref. 678 with permission.)

Sustained-release, wax-based nifedipine tablets exhibited a change in drug release after storage. Formation of nifedipine microcrystals and structural changes in the wax vehicle were given as explanations for the observed change.686 Solid dispersions of griseofulvin prepared with polyethylene glycol 3000 (PEG 3000) showed a decreased dissolution rate of griseofulvin after storage, which was ascribed to the crystallization of PEG 3000.687 This change in drug release was inhibited by addition of the surfactant sodium dodecyl sulfate to the formulation.

4.2.2.2. Changes in Drug Release from Coated Dosage Forms

The stability of the drug release characteristics of film-coated tablets and pellets is affected by the stability of the films. This should be the case especially when the film contributes significantly to the rate-limiting step in the release. The stability of a film coat

Drawing Liles Train

time (min)

Figure 166. Changes in the dissolution rate of calcium 4-aminosalicylic acid after storage. The curves represent the dissolution rates before storage (o), after storage for 8 (A), 16 (a), and 24 days (□) at 23°C and 32.9% RH, and after storage for 8 16 (•), and 24 days (■) at 23°C and 92.9% RH. (Reproduced from Ref. 682 with permission.)

time (min)

Figure 166. Changes in the dissolution rate of calcium 4-aminosalicylic acid after storage. The curves represent the dissolution rates before storage (o), after storage for 8 (A), 16 (a), and 24 days (□) at 23°C and 32.9% RH, and after storage for 8 16 (•), and 24 days (■) at 23°C and 92.9% RH. (Reproduced from Ref. 682 with permission.)

prepared from an aqueous polymeric dispersion was affected by the curing process.688 Drug release from enteric-coated and sugar-coated tablets was more susceptible to the effect of humidity than that from film-coated tablets. For example, storage of sugar-coated tablets changed the disintegration time, leading to increased689 or decreased dissolution rate.690 691 Enteric-coated aspirin tablets exhibited a decrease in dissolution rate during storage at 33°C and 60% RH, as shown in Fig. 167.692 A similar decrease in dissolution rate is reported for sugar-coated chlorpromazine tablets.693

Although drug release from film-coated tablets is generally more stable than that from enteric-coated and sugar-coated tablets, the release rates may change depending on storage conditions. For example, film-coated chlorpromazine tablets exhibited a change in drug release at temperature conditions cycling between 30°C and room temperature.693 Storage of tableted microencapsulated aspirin granules prepared with polyacrylate-polymethacry-late-based polymers resulted in decreased drug release with storage time, an effect ascribed to cross-linking of the polymer leading to prolonged disintegration time.694

4.2.2.3. Changes in Capsule Shells with Time and Storage Conditions

Capsules prepared from gelatin are physically unstable at water contents outside the range of 12-18%. Storage of two chloramphenicol capsules at high humidity prolonged the disintegration time and decreased the drug release rate, as shown in Fig. 168.695 Decrease in the drug release from ampicillin capsules during storage at high humidity was suggested to be due to the agglomeration of drug particles caused by moisture.696

Drug release from capsules may change owing to the reaction of the capsule shells with the contents. A decrease in the drug release rate from capsules containing polysorbate 80 was explained by assuming that cross-linking of gelatin was promoted by formaldehyde formed from the oxidation of polysorbate 80.697 Interaction of dyes and gelatin in capsule shells, especially under light, could change the rate of drug release from capsules.698 699 These

time (min)

Figure 167. Changes in the dissolution rate of enteric-coated aspirin tablets after storage. The curves represent the dissolution rates before storage (O) and after storage at 33°C and 60% RH for 10 (■), 20 (▲), and 42 days (•). (Reproduced from Ref. 692 with permission.)

time (min)

Figure 167. Changes in the dissolution rate of enteric-coated aspirin tablets after storage. The curves represent the dissolution rates before storage (O) and after storage at 33°C and 60% RH for 10 (■), 20 (▲), and 42 days (•). (Reproduced from Ref. 692 with permission.)

Figure 168. Changes in the dissolution rate of two different chloramphenicol capsules at 49% RH (a) and 66% RH (b). The curves represent the dissolution rates before storage (x) and after storage for 2 (•), 18 (O), and 16 weeks (A). (Reproduced from Ref. 695 with permission.)

changes were enhanced by combinations of the effects of high humidity and light, suggesting a contribution of photoreaction(s) to the changes seen.698 These detrimental effects were eliminated when dissolution was tested in simulated gastric and intestinal fluids with pepsin and pancreatin, respectively (Fig. 169).700 Gelatin-coated acetaminophen tablets exhibited a marked decrease in dissolution rate during storage at high humidity (30°C, 80% RH), which was moderated by the addition of pancreatin to the dissolution medium (Fig. 170).701 Presumably, the addition of pancreatin helps to cleave the cross-linked gelatin. Decreases in disintegration and release rate were also reported for ketoprofen rectal capsules upon storage.702

time (min)

Figure 169. Effect of added enzymes on the decrease in the dissolution rate of gelatin capsules containing dyes after storage under fluorescent light for 2 weeks at 80% RH. Open symbols represent capsules without enzyme; filled symbols represent capsules with added pancreatin (0.9%).D, ■, Chocolate brown opaque capsules; O, bright blue opaque capsules. (Reproduced from Ref. 700 with permission.)

time (min)

Figure 169. Effect of added enzymes on the decrease in the dissolution rate of gelatin capsules containing dyes after storage under fluorescent light for 2 weeks at 80% RH. Open symbols represent capsules without enzyme; filled symbols represent capsules with added pancreatin (0.9%).D, ■, Chocolate brown opaque capsules; O, bright blue opaque capsules. (Reproduced from Ref. 700 with permission.)

Figure 170. Effect of added enzymes on the decrease in the dissolution rate of gelatin-coated acetaminophen tablets during storage. Solid curves represent tablets without enzyme; dashed curves represent tables with added pancreatin 1%). Before storage; o, after 7-month storage at room temperature; after 7-month storage at 37°C and 80% RH. (Reproduced from Ref. 701 with permission.)

Figure 170. Effect of added enzymes on the decrease in the dissolution rate of gelatin-coated acetaminophen tablets during storage. Solid curves represent tablets without enzyme; dashed curves represent tables with added pancreatin 1%). Before storage; o, after 7-month storage at room temperature; after 7-month storage at 37°C and 80% RH. (Reproduced from Ref. 701 with permission.)

4.2.2.4. Prediction of Changes in Dissolution

It is difficult to describe changes in dissolution or drug release rates during storage by kinetic equations because of the complicated and varied mechanisms involved. However, some attempts have been made, and various empirical relationships noted. The disintegration time of tablets containing gelatin as a binder followed an unusual relationship with time of storage, as shown in Fig. 171.703 Plotting the logarithm of a dissolution rate constant for prednisolone tablets versus storage time yielded a linear relationship (Fig. 172), thus allowing one to predict the dissolution rate for this formulation after any given storage time. Similarly, a relationship was seen between dissolution rate and water content such that

storage time (week)

Figure 171. Changes in the disintegration time of difenamizole tablets containing gelatin as a binder during storage at 40°C. Water content: 5.02%; 5.70; 6.01%; 6.48%. The ratio of the disintegration time after storage ( t) to that before storage (to) is plotted versus storage time. (Reproduced from Ref. 703 with permission.)

0 28 56

storage time (day)

Figure 172. An apparent log-linear relationship between the change in the dissolution rate of prednisolone tablets and storage time at 4°C. Water content: 5.41%. The ratio of the dissolution rate after storage (k) to that before storage (k0) is plotted versus storage time. (Reproduced from Ref. 704 with permission.)

0 28 56

storage time (day)

Figure 172. An apparent log-linear relationship between the change in the dissolution rate of prednisolone tablets and storage time at 4°C. Water content: 5.41%. The ratio of the dissolution rate after storage (k) to that before storage (k0) is plotted versus storage time. (Reproduced from Ref. 704 with permission.)

changes in water content with time in various packagings permitted prediction of dissolution changes upon storage.704

Changes during storage in the moisture permeability of cellulose acetate films used to effect controlled release (Fig. 173) were predicted from changes in mechanical properties of the films.705 The mechanical properties measured were relaxation time versus mechanical stress.

For model tablets coated with polymer films composed of ethyl cellulose and hy-droxypropyl methyl cellulose phthalate, plotting the logarithm of moisture permeability and dissolution rate versus the logarithm of physical aging time yielded a linear relationship (Fig. 174). This suggested that long-term stability of moisture permeability and dissolution rate can be estimated from this empirical algorithm.706

Figure 173. Changes in the moisture permeability of cellulose acetate film during storage at 100°C. (Reproduced from Ref. 705 with permission.)

log storage time (h)

Figure 174. A log-log relationship between the change in dissolution rate of hydroxypropyl methyl cellulose phthalate-coated tablets and storage time at high temperature (80°C). □, lObserved; ■, predicted. (Reproduced from Ref. 706 with permission.)

log storage time (h)

Figure 174. A log-log relationship between the change in dissolution rate of hydroxypropyl methyl cellulose phthalate-coated tablets and storage time at high temperature (80°C). □, lObserved; ■, predicted. (Reproduced from Ref. 706 with permission.)

It is generally accepted that the stability of dissolution rate during room-temperature storage cannot be predicted from shorter-term storage under accelerated conditions of high temperature and humidity. This was confirmed by the observation that tablets containing polyvinylpyrrolidone exhibited a marked change in dissolution rate during storage at 23 °C, whereas no change was observed at 65°C.683 On the other hand, short-term accelerated testing is considered to be somewhat useful. Changes in the dissolution rate of hydrochlo-rothiazide tablets at room temperature, for example, were correlated to changes observed at 37, 50, and 80°C, suggesting that stability evaluation by accelerated testing may be possible in some cases.675 That no change was seen in dissolution rate during short-term storage of film-coated, enteric-coated, and sugar-coated tablets under accelerated conditions provided some confidence that dissolution at room temperature should not change significantly with time.693

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