INTRODUCTION:

In recent years, there has been a very active debate about the stability of drug products especially after exceeding the expiry dates. The regulatory authorities require comprehensive stability data for market approval. The shelf-life obtained, (which is defined as the time interval that a drug product is expected to remain within the approved shelf life specification provided that it is stored under the conditions defined on the label in the proposed containers and closure³), determines the expiry date, which is typically between 1 and 5 years and commonly set in a conservative manner⁴.

But what about the stability of drug products before the end of their shelf life within 1, 2 or 3 months, does the pharmaceutical product remain effective during this last 3 months especially last month, or the quantity of the active ingredient decreases during this period, to find out we conducted this study during the last year of the expiry date and examined the pharmaceutical products every 3 months until the end of their shelf life.

Stability of a pharmaceutical product may be defined as the capability of a particular formulation in a specific container/closure system to remain within its physical, chemical, microbiological, toxicological, protective and informational specifications. In other words, it is the extent to which a product retains, within the specified limits, throughout its period of storage and use, the same properties and characteristics possessed at the time of its packaging⁵.

Stability is an important factor which is directly related with the quality, safety and efficacy of a drug product. A drug product which is not having sufficient stability can result in various changes in physical as well as chemical properties that are ultimately harmful to the patients⁴. Also, drug decomposition may yield toxic by-products that are harmful to the patient too⁶. For example, loss of activity up to a level of 85% of that claimed on the label may lead to failure of the therapy⁵.

The stability of drug substances mainly depends on factors like temperature, moisture, pH, oxygen, light and excipients. Temperature is one of the primary factors affecting the drug stability because most of the drug substances degraded at elevated temperature. Moisture adsorbs on to the surface of drug and forms a water layer in which it is dissolved and degraded. The oxygen concentration can affect the drug substances by oxidation process. Photodegradation depends on the nature of light source and the nature of the drug substances selected in the formulation of drug products⁵.

Drug substances used as pharmaceuticals have diverse molecular structures and are, therefore, susceptible to many and variable degradation pathways. Possible degradation pathways include hydrolysis, dehydration, isomerization and racemization, elimination, oxidation, photodegradation, and complex interactions with excipients and other drugs⁷. We chose several pharmaceutical products which might be susceptible to degradation by one of this pathways.
The NSAIDs (Nonsteroidal anti-inflammatory drugs) are a group of chemically dissimilar agents that differ in their antipyretic, analgesic, and anti-inflammatory activities. They act primarily by inhibiting the cyclooxygenase enzymes that catalyze the first step in prostanoid bio-synthesis. This leads to decreased prostaglandin synthesis with both beneficial and unwanted effects.

Aspirin can be thought of as a traditional NSAID, but it exhibits anti-inflammatory activity only at relatively high doses that are rarely used. It has gained much more usage at lower doses for the prevention of cardiovascular events such as stroke and myocardial infarction (MI)⁸. It is used to inhibit platelet aggregation. It is the most widely prescribed drug for the primary and secondary prevention of cardiovascular and cerebrovascular diseases⁹. Low-dose aspirin inhibits COX-1–mediated production of TXA2, thereby reducing TXA2-mediated vasoconstriction and platelet aggregation and the subsequent risk of cardiovascular events⁸.

Captopril is an active inhibitor of the angiotensin-converting enzyme, which reduces peripheral resistance and lowers blood pressure. It is widely used for the treatment of hypertension and congestive heart failure¹⁰. It act on the renin–angiotensin system by inhibiting the conversion of angiotensin I to angiotensin II¹¹. ACE inhibitors are first-line drugs for treating heart failure, hypertensive patients with chronic kidney disease, and patients at increased risk of coronary artery disease⁸.

Diuretics are drugs that increase the rate of urine flow. Most clinical applications of diuretics aim to reduce extracellular fluid volume by decreasing total-body NaCl content¹². The loop diuretics such as furosemide are the drugs of choice for reducing acute pulmonary edema and acute/chronic peripheral edema caused from heart failure or renal impairment⁸. Furosemide is a potent diuretic used in treatment of oedematous states associated with cardiac, renal and hepatic failure and the treatment of hypertension.

Omeprazole is a PPI (proton pump inhibitor) blocking the final common pathway of acid secretion at the luminal surface of the parietal cell by binding to H⁺K⁺-ATPase, the so-called “acid pump” or “proton pump” thereby providing potent suppression of gastric acid output¹³. There are many Indications for the use of PPI¹⁴ such as peptic ulcer disease (PUD), Helicobacter pylori, chronic nonsteroidal anti-inflammatory drug (NSAID) use, Barrett esophagitis (Gastric juice that refluxes into the oesophagus can injure oesophageal squamous epithelium. When the injury heals througha metaplastic process in which an abnormal columnar epithelium replaces the injured squamous one, the resulting conditionis called Barrett’s oesophagus)¹⁵, erosive esophagitis and Zollinger–Ellison syndrome (It is caused by a gastrin producing tumor called a gastrinoma that results in gastric acid hypersecretion)¹⁶.

H2-receptor antagonists such as ranitidine competitively and selectively inhibit the binding of histamine to H2 receptors on the basolateral membrane of the parietal cell, thereby reducing intracellular concentrations of the signaling molecule cAMP and, as a result, the secretion of acid by the parietal cell. The major therapeutic indications for H2-receptor antagonists are to promote healing of gastric and duodenal ulcers, to treat uncomplicated GERD, and to prevent the occurrence of stress ulcers¹⁷.

MATERIALS AND METHODS:

Working standards:

Working standard of captopril and furosemide were gifted by Asia industries, Aleppo-Syria. Working standard of aspirin and ranitidine were gifted by Barakat industries, Aleppo-Syria. Working standard of omeprazole was gifted by Razi industries, Aleppo-Syria.

Commercial pharmaceutical products:

Commercial pharmaceutical products were: for aspirin: Asiapirin 81mg (Asia industries), Rasperine 81mg (Razi industries), Aspirin Issa (Issa industries), Aspirex 81mg (Medico industries). Captopril: Capoten 25mg (Unipharma industries), Capotal 25mg (Alpha industries), Captophen 25mg (Ibn hayyan industries). Furosemide: Furosemid 40mg (Asia industries), Obarsix 40mg (Oubari industries), Furosemide Ugarit 40mg (Ugarit industries).

Omeprazole:

Omepral 20mg (Asia industries), Omezor 20mg (Avenzor industries). Ranitidine: Ranitidine human 150mg (Human industries), Ranitidine kimi 150mg (Kimi industries), Ranitidine Oubari 150mg (Oubari industries).

Apparatus:

The HPLC instrument used was Shimadzu LC 20-AT (Shimadzu, Kyoto, Japan) with diode array detector. A NUCLEOSIL-C18(octadecylsilane) EC- Machrey-Nagel reversed phase column (250mm × 4.6mm i.d; 5µm particle size) was used. Ultrasonic processor (Powersonic, model 405, Korea) was used to sonicate the sample solutions. The pH meter used was from Crison (Madrid, Spain).

Preparation of samples:

Preparation of standards and samples solutions:

Aspirin:

An equivalent amount of 100mg was weighted and transferred into a 10ml volumetric flask, acetonitrile for chromatography was added to fill the flask to about half of its capacity and sonicated for about 15 minutes to make sure that the active ingredients is well dissolved. Diluted with the same solvent to volume, mixed, sonicated and filtered. 1ml was taken and diluted to 10 ml with the same solvent.

Captopril:

An equivalent amount of 25mg was weighted and transferred into a 25ml volumetric flask, the mobile phase (mixture of 550ml of methanol and 450ml of water containing 0.50ml of phosphoric acid ) was added to fill the flask to about half of its capacity and sonicated for about 15 minutes to make sure that the active ingredients is well dissolved. Diluted with the mobile phase to volume, mixed, sonicated and filtered.

Furosemide:

An equivalent amount of 50mg was weighted and transferred into a 50ml volumetric flask, the diluted solution (22mL of glacial acetic acid with a mixture of acetonitrile and water (50:50) diluted to 1000mL) was added to fill the flask to about half of its capacity and sonicated for about 15 minutes to make sure that the active ingredients is well dissolved. Diluted with the diluted solution to volume, mixed, sonicated and filtered.

Omeprazole:

An equivalent amount of 30mg was weighted and transferred into a 25ml volumetric flask, the mobile phase (27ml of acetonitrile and 73ml of 1.4g/l solution of disodium hydrogen phosphate previously adjusted to pH 7.6 with phosphoric acid) was added to fill the flask to about half of its capacity and sonicated for about 15 minutes to make sure that the active ingredients is well dissolved. Diluted with the mobile phase to volume, mixed, sonicated and filtered.

Ranitidine:

An equivalent amount of 15mg was weighted and transferred into a 10ml volumetric flask, the mobile phase (mixture of 850 ml methanol and 15ml of 0.1 M aqueous ammonium acetate) was added to fill the flask to about half of its capacity and sonicated for about 15 minutes to make sure that the active ingredients is well dissolved. Diluted with the mobile phase to volume, mixed, sonicated and filtered.

RESULTS:

In order to assure the stability of the studied pharmaceutical products, the percentage of the active ingredients concentrations remaining were determined during the last year of their shelf life by comparing them with working standards.

Aspirin:

An HPLC method based on the European Pharmacopoeia was used. The mobile phase consisted of ²400ml acetonitrile for chromatography, 600ml of water and 2ml of phosphoric acid. The flow rate was 1ml/min, the detection wavelength was 237nm and the temperature was 26C^o.

Table 1: The Percentage and quantity of the active ingredients of aspirin pharmaceutical products during first, second, third and last three months of their shelf life

Commercial products	Percentage of API during the first 3 months	RSD^*	Percentage of API during the Second 3 months	RSD^*	Percentage of API during the Third 3 months	RSD^*	Percentage of API during the Last 3 months	RSD^*
Asiapirin 81mg	100.51%	0.496176456	100.31%	0.65774289	98.39%	0.687529764	95.89%	0.55364592
Rasperine 81mg	97.44%	0.694425458	97.11%	0.130952877	96.79%	0.699050627	93.34%	0.247272135
Aspirin Issa 81 mg	103.03%	0.092866368	102.75%	0.061231572	101.98%	0.324092306	97.26%	0.1236908
Aspirex 81mg	-*	-	-	-	94.03%	0.067493318	91.17%	0.350552059

*n=2 , * Aspirex was studied during the last six months

API= Active Pharmaceutical Ingredient

Fig. 2: The percentage of aspirin during first, second, third and last 3 months of its shelf life and a chromatogram of aspirin pharmaceutical product

Table 2: The Percentage and quantity of the active ingredients of captopril pharmaceutical products during first, second, third and last three months of their shelf life

Commercial products	Percentage of API during the first 3 months	RSD^*	Percentage of API during the Second 3 months	RSD^*	Percentage of API during the Third 3 months	RSD^*	Percentage of API during the Last 3 months	RSD^*
Capoten 25mg	94.35%	0.20111	93.61%	0.832837	92.58%	0.024975	92.52%	0.063358
Capotal 25mg	103.09%	1.017128	102.21%	0.083009	101.62%	0.5321	99.44%	1.379928
Captophen 25mg	-*	-	-	-	97.88%	0.360084	95.32%	0.779113

Fig.3: The percentage of captopril during first, second, third and last 3 months of its shelf life and a chromatogram of captopril pharmaceutical product

Table 4: The Percentage and quantity of the active ingredients of omeprazole pharmaceutical products during first, second and last three months of their shelf life

Commercial products	Percentage of API during the first 3 months	RSD^*	Percentage of API during the Second 3 months	RSD^*	Percentage of API during the Last 3 months	RSD^*
Omepral 20mg	103.50%	0.974303707	103.10%	1.479112	102.35%	0.811437
Omezor 20mg	104.78%	0.276895152	103.61%	1.100627	103.24%	1.224274

Fig.5: The percentage of omeprazole during first, second and last 3 months of its shelf life and a chromatogram of omeprazole pharmaceutical product

Table 5: The Percentage and quantity of the active ingredients of ranitidine pharmaceutical products during first, second and last three months of their shelf life

Commercial products	Percentage of API during the first 3 months	RSD^*	Percentage of API during the Second 3 months	RSD^*	Percentage of API during the Last 3 months	RSD^*
Ranitidine Human 150mg	108.67%	1.168315997	106.64%	0.350467	98.25%	1.09878924
Ranitidine Kimi 150mg	107.61%	0.403837536	106.25%	0.477224	95.09%	1.23343858
Ranitidine Oubari 150 mg	108.16%	0.025797162	107.84%	0.765458	98.68%	0.92297265

Fig.6: The percentage of ranitidine during first, second, third and last 3 months of its shelf life and a chromatogram of ranitidine pharmaceutical product

Ranitidine:

An HPLC method based on European Pharmacopoeia was used. The mobile phase consisted of ¹a filtered and degassed mixture of 850ml methanol and 15 ml of 0.1 M aqueous ammonium acetate. The flow rate was 1ml/min, the detection wavelength was 322 nm and the temperature was 26C^o.

DISCUSSION:
The results obtained were discussed by reference to the USP pharmacopoeia. The pharmacopoeia recommended that tablets should contain not less than 90.0 percent and not more than 110.0 percent of the labeled amount of aspirin, captopril, furosemide, ranitidine and omeprazole.

As for aspirin the active ingredient of the commercial pharmaceutical products during the last 3 months were within the ratio of (91.17% - 97.26%). The chemical structure reveals that aspirin is an ester moiety, which is very susceptible to hydrolysis under different hydrolytic conditions. Aspirin is known to undergo decomposition by hydrolysis into Salicylic acid, when exposed to moisture. It is reported that the decomposition reaction is promoted at high temperature, in alkaline solutions, even in the presence of magnesium salt. The known impurities of aspirin are already reported, which includes salicylic acid, salsalate (salicylsalicylic acid), acetylsalicylsalicylic acid, 4-hydroxybenzoic acid, 4-hydroxyisophthalic acid and acetylaalicylic anhydride.¹⁸

As for captopril the percentage was (92.52% - 99.44%). Captopril has a thiol group in its structure that makes it susceptible to oxidation. Major oxidative product of captopril was identified as captopril disulfide along with trace amount of the hydrolyzed product, L-proline¹⁹. As the captopril molecule also includes an amide function, degradation via hydrolysis is possible.²⁰

The percentage of furosemide was between (91.45% - 97.23%). Furosemide has a reactive nitrogen in its structure that makes it susceptible to hydrolysis²¹. It is hydrolyzed in acidic media to form 4-chloro-5-sulfamoylanthranilic acid (CSA). It is also recognized as a photosensitive drug, its concentration might also be lower if protection from light has not been taken into consideration²².

The remaining percentage of omeprazole active ingredient was (102.35% - 103.24%). The influence of heat and acidic pH on the degradation of omeprazole has been observed and the changes in the concentration were monitored by UV spectrophotometry, it also shows high sensitivity relative air humidity. This drug is very sensitive to heat and acidic environment. Degradation was conducted on both neat solution and pharmaceutical formulation^23,24,25.

Ranitidine (95.09% - 98.68%). For a hygroscopic drug such as ranitidine, which absorbs moisture from the environment, its physical and chemical instability in the presence of moisture has a major impact on the choice of formulation excipients, the selection of processing method, and the design of the product package²⁶. Also the effect of moisture and humidity on the degradation kinetics of ranitidine hydrochloride has been reported⁷.

The results demonstrated here showed that all these percentages were within the acceptance criteria of the USP pharmacopoeia, so these pharmaceutical products stayed stable under appropriate storage conditions.

In compared with other researches:

Bello S. S. and Mudi I compared three brands of Aspirin sold in Sokoto State during their shelf life, after the assay test brands A and B failed with percentage contents of 117.130% and 127.942% respectively. Only brand C passed the test, giving a 102.714 % content of aspirin.²⁷

Mansour O. Isbera M. Ismail G. and Mayya G. studied the effect of temperature and moisture on the physical and chemical stability of furosemide tablets marketed in Syria. The tablets were exposed to different values of relative humidity and temperature according to climatic conditions across 12 months. The content of tablets in all studied brands was decreased to values less than 90% (USP specifications for drug content) after (11, 9, 5) months for (A, B, C) brands. They reported that furosemide tablets, when stored in inappropriate storage condition especially in coastal area weather of Syria that usually is in high humidity which cause acceleration changes on the physical and chemical properties leading to less effective drug.²⁸

El-Sayed A. Boraie N.A. Ismail F.A. El-khodagui L.K. and Khalil S.A assessed the pharmaceutical quality of 7 local omeprazole capsules brands in Egypt. Products were subjected to a 3 month stability study. The drug content of the tested brands was within the acceptable range (90%–110%) at the end of 2 months storage, except for brand B which showed a drastic decrease to 1.79%. After 3 months, 3 other brands, A, D and F, in addition to brand B, failed to maintain omeprazole content above 90%. The initial omeprazole content of brand C was higher than the upper limit of the acceptable range (121.02%); this decreased after 2 and 3 months storage to 103.6% and 102.33% respectively.²⁹

Sarker M. R., Rashid S, Raju A A, Rana M, Bin Karim M. F, Akter R, Abu Nayem Md., Al-Noman Howlader, Ming L. S, Ismail N. E. study was aimed to assess the pharmaceutical quality of ranitidine hydrochloride tablets manufactured in Bangladesh. Tablets were collected from different parts of Bangladesh and quality parameters were evaluated according to the United States Pharmacopoeia and the British Pharmacopoeial methods.

Among 43 brands tested, 8 failed to comply with the USP specification (active ingredient: 90±10%) due to containing of less amount of ranitidine of which 6 brands were spurious and 2 were substandard in nature.³⁰

Hayder Hamed Abed investigated an Iraqi manufactured Captopril tablets (uncoated 25mg.) in term of shelf life in a different accelerated stability condition. Three different batches of studied tablets were selected and stored for accelerated stability conditions. The concentrations of API were between 104.255 – 103.896%.³¹

CONCLUSION:
Five pharmacopoeial HPLC methods were applied on five different pharmaceutical products to determine the quantity of their active ingredients before the end of their shelf life.

The results presented in this paper showed that:

The active ingredient concentration of these pharmaceutical products decreased during the last 3 months of their shelf life, but it remains within the acceptance criteria of the USP pharmacopoeia (90-110%).

Theses pharmaceutical products remain therapeutically effective considering appropriate storage conditions, despite the diminishing of their content slightly over time.

ACKNOWLEDGEMENT:

This research work was supported by University of Aleppo.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 20.05.2019 Modified on 24.06.2019

Research J. Pharm. and Tech. 2019; 12(12): 6111-6118.

DOI: 10.5958/0974-360X.2019.01062.X

Commercial products	Percentage of API during the first 3 months	RSD^*	Percentage of API during the Second 3 months	RSD^*	Percentage of API during the Third 3 months	RSD^*	Percentage of API during the Last 3 months	RSD^*
Furosemid 40mg	102.786%	0.593861	100.17%	0.195218	98.65%	0.818299	97.23%	0.761031
Obarsix 40mg	97.440%	0.018768	93.76%	1.966346	92.07%	0.84407	91.45%	1.523741
Furosemide Ugarit 40mg	96.567%	0.27159	93.89%	1.066725	92.62%	0.70266	91.84%	1.327156