A comparative evaluation of the quality of ten generic telmisartan tablets with the brand

The objective of this study was to comparatively assess the quality of generic Telmisartan tablets with the brand. Mean drug content and impurities determination, dissolution tests and solubility tests in four different media were performed on ten Telmisartan generics and the brand Micardis. High performance liquid chromatography was used in the determination of Telmisartan content, impurities and solubility of Telmisartan in the tablets and dissolution apparatus II was used for dissolution tests. Four generics showed poor solubility and dissolution rate in water, pH 7.5 and pH 4.5; three of them having a relatively huge number of impurities compared to the brand. The other six generics showed more or less the same mean drug content, dissolution rate as that of the brand and a better solubility. Three generics showed to have a comparable number and amount of impurities as that of the brand. The dissolution profiles of four generics were comparable to that of the brand in two different dissolution media out of the four media used in the dissolution tests. This study showed that while some generics may be of inferior quality to that of their brand counterparts, others can be of approximately the same quality as that of the brand.


INTRODUCTION
Telmisartan is a potent and selective Angiotensin II receptor (type AT1) antagonist with no agonist activity.It is used for the management of essential arterial hypertension.Telmisartan is highly lipophilic and practically insoluble in water, its solubility in aqueous media is greatly influenced by pH.In the range of pH 3-9, Telmisartan is simply poorly soluble in water; the maximum solubility can only be attained at low and high pH.Telmisartan exhibit polymorphism-mainly existing in either polymorph A or B (Wienen et al., 2000;Tran et al., 2008).
Generic drugs are copies of their brand name counterparts which are pharmaceutically equivalent and bioequivalent to their brand name twins.Two drugs are pharmaceutically equivalent if they contain the same amount of the same active ingredient, are identical in dosage form and route of administration, labeled for the same indication and are produced under similar purity and quality standards.On the other hand, bioequivalent drugs must have a comparable rate and extent at which the active ingredient is made available at the site of action (Howland, 2009).Pharmacokinetics parameters used to measure the bioequivalence between two drugs are area under the plasma concentration-time curve (AUC) which determines the extent of absorption in a given time and the maximum plasma concentration (Cmax) which appraises the rate of absorption.Bioequivalence is the key for approving generic drugs, and is determined by the ratio of the generic AUC and Cmax to that of its brand name to be between 80%-125% range with a 90% confidence interval.The assumption is that, if the brand and the generic drug will have a similar rate and extent at which the active ingredient is made available at the site of action, they will therefore have similar therapeutic effects (Howland, 2010;Kefalas and Ciociola, 2011).WHO (2004) estimated that 30% of the world's population lack regular access to essential medicine, with high costs and poor availability of medicines being the main reasons (Babar et al.,2007;Nguyen et al.,2009).As a strategy to reduce the costs and the amount of money used to buy pharmaceuticals, many countries promote the use of generic drugs (King and Kanavos, 2002).This strategy to contain drug expenditure seem to work best for those patients suffering from chronic diseases like hypertension as there is a possibility for the patients to remain under medication for the rest of their life (Shrank et al., 2011;Van Mourik et al., 2010).This effort to reduce drug expenditure is undermined by the belief that generic drugs are inferior in quality and safety to their brand name drugs (Berg et al., 2008;Shrank et al., 2011); some people even doubting if the process used to approve generic medicines can guarantee the efficacy and safeness of generic drugs (Blier, 2007).
Generic drugs can contain different excipients from those used in their brand name counterparts.Excipients are inactive materials mixed together with the active ingredient of the drug product to easy manufacturing process and improve the performance of the product (Shah et al., 2010).These excipients can affect the pharmaceutical characteristics of the drug product either positively or negatively.Chen et al (2006) observed that the AUC and Cmax of ranitidine were decreased by 50 and 45% respectively when sorbitol instead of sucrose was used as a sweetening agent.Even though sorbitol was shown to have no effect on the AUC of metoprolol the Cmax of metoprolol was reduced by 23%.This shows that though two drugs might be containing the same active ingredient, from the concept that they contain different types or different amount of the same excipient, these two drugs might have different pharmaceutical properties which might influence the drugs' in vivo performance.
Usually after the patent of the brand drug have expired, the brand company does not disclose its manufacturing processes.This means that sometimes the generic drug company and the brand drug company might be using different manufacturing processes to manufacture the same drug which may affect the quality and purity of the drug product.Drugs with poor quality could be fatal to the well-being of the society and sometimes can lead to the development of drug resistant strains (Wernsdorfer, 1994).Drugs with little or no active ingredient and those drugs with poor dissolution rate will actually not be able to cure the intended disease; whereas those with excessive active ingredients and impurities can cause adverse effects to the patients (Po, 2001).The pharmaceutical quality of the drug product usually prognosticates the in vivo performance of the product -poor pharmaceutical quality will mean poor in vivo performance of the product.Since the motive to choose generic drugs over brand name drugs is to reduce medical costs, generic drugs can sometimes be even more costly if they are of poor quality.Thus the present study aimed at comparatively evaluating the quality of generic Telmisartan tablets against the brand.

Mean content determination
The mean content of Telmisartan in the tablets was determined by using high performance liquid chromatography (HPLC) method (Shimadzu, LC-10AT vp-Japan).This is a USP method (Telmisartan tablets Revision bulletin, 2011) modified to suit our specifications.20 Telmisartan tablets were weighed, average calculated and then powdered.The powder equivalent to 8 mg of Telmisartan was weighed, then transferred into100 ml volumetric flask.About 70 ml of the diluent was added then sonicated for 5 min to dissolve the Telmisartan completely and the volume made up to the mark with the diluent.It was well mixed by sonication for further 5 min and a portion of the solution was filtered through 0.45 μm filter then injected into the HPLC analytical column C8 (5 μm, 4.6×150 mm), the elutes were monitored at 298 nm.The mobile phase consisted of methanol and ammonium dihydrogen phosphate (65:35) at the flow rate of 1 ml/min.The phosphate buffer was prepared by dissolving 2 g of ammonium dihydrogen phosphate in 1000 ml of distilled water then the final pH was adjusted to 3.0 using 1 M phosphoric acid.The mobile phase was filtered through 0.45 μm Nylon membrane thereafter was degassed by sonication.0.005 N of methanolic solution of NaOH was used as a diluent.The HPLC method was validated for linearity, accuracy and precision.
The brand drug was obtained from the manufacturer and the generic drugs were bought from community pharmacies.All the generic drugs were from the Chinese pharmaceutical companies as shown in Table 1, all the drugs had a shelf life of more than a year when they were tested.

Linearity
The linearity response was determined by preparing and injecting solution with concentration of 0.04, 0.064, 0.08, 0.096 and0.16 mg/ml of standard Telmisartan.

Precision
Precision was measured in terms of repeatability of application and measurement by preparing and injecting the standard solution of 0.08 mg/ml of Telmisartan six times (Figure 5 to 7).

Accuracy
Accuracy (recovery) study was performed by spiking 80, 100, and

Solubility studies
Powder equivalent to 20 mg of Telmisartan was dissolved in 1 ml of the appropriate respective buffer (pH 1.2,4.5,7.5 or water) in which the solubility of the Telmisartan was to be determined and kept at 37°C for 48 h.Thereafter, the resulting solution was centrifuged and diluted accordingly, filtered and injected into the HPLC to determine the amount of Telmisartan dissolved.

Impurities determination
For the number of impurities in each tablet; tablet powder equivalent to 8 mg was dissolved in 8 ml diluent then a portion of the solution was filtered and injected into the HPLC.The remained portion was diluted 1000 times, filtered then injected into the HPLC to determine the amount of Telmisartan in the solution which was then used to determine the percentage of each impurity in the tablet when compared with the total amount of Telmisartan contained in the tablet.

Dissolution test
The stock solution of standard Telmisartan was diluted using the appropriate buffer (pH 1.2, 4.5, 7.5 or water) to obtain solutions containing 0.003, 0.004, 0.005, 0.011, 0.016 and 0.021 mg/ml of Telmisartan.The absorbances of these solutions were measured at 291, 296, 297 and 298 nm on a UV-spectrophotometer when pH 1.2, 4.5, 7.5 and water was used, respectively; and the buffer of the respective media was used as a blank.The linearity was established over the entire concentration range by plotting a graph of absorbance versus the corresponding concentrations in each of the used buffer; the data were statistically evaluated using linear regression analysis and the method was found to be precise.

Mean content of Telmisartan in the tablets
Before it was used for determination of the mean content of Telmisartan in the samples, the HPLC method was validated for linearity, precision and accuracy; results are shown in Tables 2, 3, and 4. The USP (Telmisartan tablets Revision bulletin, 2011) requires the mean content of telmisartan in telmisartan tablets to be not less than 95% and not more than 110%.The mean contents of telmisartan in all the tablets were within the required range as shown in Table 5.

Impurities determination result
Generic 1 was found as having a huge number of impurities, followed by generic 9, 5 and 4, whereby generic 2, 3, and 6 had the lowest number of impurities.
The USP states that individual impurities should not be more than 0.2% of the Telmisartan amount in the tablet (Telmisartan tablets Revision bulletin, 2011).Using this criteria, generic 8 had 2 impurities and generic 4, 9 and 10 had 1 impurity each which were out of the USP acceptance criteria.The brand had the smallest total percentage of all impurities followed by generic 2 and 6.On the other hand, generic 9 had the largest total percentage of all the impurities coming after generic 8 and 10, as demonstrated in Table 6.

Solubility determination results
The tablets of the brand and generic 1, 4 and 7 showed a significant high solubility in water and pH 7.5 followed by generic 3 in the same media.The solubilities of all the generics and the brand were worse in pH 4.5 media contrary to their solubilities in pH 1.2 media which were a little bit better (Table 7).

Dissolution in pH 7.5 buffer
Four generics showed poor dissolution rates in this buffer.The USP (Telmisartan tablets Revision bulletin, 2011) requires that not less than 75% of the labeled amount is dissolved within 30 min; for these four generics the cumulative percent of Telmisartan dissolved was less than 20% after 60 min.The other seven companies released more than 80% of the labeled amount in 60 min as shown in Figure 1.

Dissolution in water
Six generics and the brand had more than 75% dissolved in 30 min, the remaining four generics showed a poor dissolution rate with three of which releasing less than 10% in 60 min.Its illustrations are indicated in Figure 2.

Dissolution in a pH 4.5 buffer
Almost all the companies showed insufficient dissolution rates in this dissolution buffer, probably due to the low solubility of the drug in this media.Only three generics released more than 50% of the labeled amount with generic 1 being superior to all other generics including the brand as shown in Figure 3 and 4. The dissolution rate of four generics was so low that the amount of Telmisartan dissolved was lower than the range in the calibration curve used for measurements so they were not included in the dissolution profile.

Dissolution in pH 1.2 buffer
Although all the companies except one had more than 80% of the labeled amount dissolved after 60 min, only four companies released more than 75% of the labeled amount in 30 min.Generic 3 released less than 40% in 60 min.On the other hand, generic 5, 9, 10 and 2 showed fast dissolution rates such that in 10 min the dissolutions were more or less complete.

Dissolution profiles similarity
F 2 values were calculated using the equation below to check the similarity of the dissolution profiles of the generic companies when compared to that of the brand.Two dissolution profiles are said to be comparable if the Where, n stands for the number of time points and t is the time under consideration.R is the reference drug and T is the test drug.
In pH 7.5 and 4.5 buffers, only generic 3 and generic 8, respectively, had comparable dissolution profiles as that of the brand.Generics 1, 4 and 7 had a similar drug release profile as that of the brand in both water and pH 1.2 buffers.Then again generic 3 and generic 6 had comparable profiles only in water and pH 1.2 buffers, respectively.There was no generic drug which had a similar profile to that of the brand in all the four media (Table 8).

DISCUSSION
Even though the mean content of all the samples were within the specified range, some of the samples showed insufficient dissolution rates.Four generics (generic 2, 5, 9 and 10) showed poor dissolution rates in water, pH 4.5 and 7.5 buffers which collaborated with their solubilities in these media.Fast dissolution rate shown by most of the samples in pH 1.2 buffers predicts easy dissolution of these tablets in the stomach which has approximately the same pH.In a study of absorption of Telmisartan in rats, a very small amount of Telmisartan was observed to be absorbed in the stomach and the absorption was somewhat decreased by food intake (Shimasaki, 1999).In this account, even though it might not be the same in human, those generics with high dissolution rate in the acidic media and poor dissolution rate in other media, their absorption and hence their bioavailability can be affected by anything which can raise the stomach pH (Horter and Dressman, 2001;Ming et al., 2009).
The use of different excipients or using the same excipients in different ratios might be one of the reasons for the observed differences in solubilities and dissolution rates among the samples.For instance, the type and amount of disintegrant used (Ahmed et al., 2000), the mode of incorporation of the disintegrant into the drug formulation (Rahman et al., 2011) and the effect of pH on the disintegrant (Zhao and Augsburger, 2005) can affect the disintegration rate of the tablet, consequently affecting its dissolution rate.In an attempt to optimize a formulation containing Telmisartan, Pandya and Chaudhari (2012) showed that using different alkalizers at different ratios affected the solubility and so dissolution of the Telmisartan formulation.Differences in the stability of drug products can also cause significant differences in drug content and in vitro drug release profiles especially after the drug products has been exposed to high temperature and humidity conditions (Twagirumukiza et al., 2009;Lima et al., 2008).Impurities can cause side effects and sometimes can be fatal to the patient.The fact that the tablets showed different number of impurities in different percentages, some of which exceeding the allowed amount, suggests that these companies have different sources of active ingredient with different impurity profiles.Increased amount of impurities in a drug product may introduce unforeseen effects which might affect the drug efficacy and safety such as drug-drug interactions, patient-drug interaction to mention but a few.
The brand and 70% of the generic samples showed sufficient dissolution rate in pH 7.5 buffers and water and some of the generics showed a better dissolution rate than that of the brand in pH 1.2 and 4.5 buffers.Though there was no any generic drug which had a comparable dissolution profile as that of the brand in all the four media, similarity factor revealed that four generics had a comparable profile as that of the brand in two different media as shown in the results.This is different from the results obtained by Patel et al. (2010) in which no generic showed a similar dissolution profile as that of the brand in any of the media used.In pH 7.5 buffer and water, three generics showed high solubilities as that of the brand, whereby in pH 1.2 and 4.5 buffers, some of the generics demonstrated better solubilities than that of the brand.In spite of having the lowest total percentage of all the impurities put together, three generics a lower number of impurities than the brand and approximately the same total percentage of all impurities combined together.This implies that, some generics in some areas have an approximately the same quality as that of the brand, and sometimes generic drugs in some areas are of better quality than the brand.
This study had some limitations.One of which was the use of in vitro dissolution test as a replacement for in vivo bioavailability.Even though good dissolution may indicate good bioavailability but poor dissolution does not always mean poor bioavailability, the latter should be supported by in vivo bioavailability tests.The unknown storage conditions of the tablets before they were bought might have influenced the results.Since the same four generics showed poor dissolution rate in three media and better dissolution rates in one medium, this limitation is less important.On top of all that, excipients used in the formulations and the impurities were not identified and studied as they can greatly influence the quality and safety of the drug product.

Conclusion
Four (generic 2,5,9,10) out of ten generics, even though showed fast dissolution rates in pH 1.2 buffer, their dissolution rates in the other dissolution media were insufficient, including pH 7.5 which is the recommended buffer in the United states pharmacopeia; their dissolution profiles were not comparable to that of the brand in any of the buffers used.The four generics demonstrated poor solubilities in all the media and a relatively huge number of impurities were observed in these generics.This connote that the quality of these four generics is questionable and hence the call for post marketing surveillance as away to make sure that drugs are always safe and effective.

ABBREVIATIONS
AUC, Area under the plasma concentration-time curve; Cmax, maximum plasma concentration; HPLC, high performance liquid chromatography.

Figure 1 .
Figure 1.Comparative dissolution profiles of eleven Telmisartan tablets manufactured by different companies in phosphate buffer (pH 7.5).

Figure 2 .
Figure 2. Comparative dissolution profiles of eleven Telmisartan tablets manufactured by different companies in distilled water.

Figure 3 .
Figure 3. Comparative dissolution profiles of eleven Telmisartan tablets manufactured by different companies in phosphate buffer (pH 4.5).

Table 1 .
Companies of the Telmisartan tablets involved in the study.
120% of Telmisartan working standard solution to a preanalysed sample.The accuracy of the analytical method was established in triplicate.

Table 2 .
Summary of HPLC method validation.

Table 5 .
Mean content of Telmisartan in the tablets.
f 2 value is within the 50-100 range.