Formulations and Evaluation of Fast Disintegrating Tablets of Amlodipine Besylate: A Comprehensive Review

Abstract

Fast disintegrating tablets (FDTs) have revolutionized oral drug delivery by offering rapid disintegration and dissolution in the oral cavity without the need for water, thus enhancing patient compliance and convenience, especially in pediatric, geriatric, and dysphagic populations. Amlodipine Besylate, a widely used calcium channel blocker for hypertension and angina, often encounters challenges related to bitter taste, poor aqueous solubility, and delayed onset of action in conventional dosage forms. Formulating Amlodipine Besylate as an FDT can overcome these issues by enabling faster disintegration, improved palatability, and potentially enhanced bioavailability. This review comprehensively examines various formulation strategies, including the selection of superdisintegrants, binders, fillers, and taste masking techniques, alongside different preparation methods such as direct compression, wet granulation, and sublimation. The evaluation parameters critical for FDTs such as disintegration time, hardness, friability, dissolution profile, and stability are discussed in detail. Additionally, recent advancements like the use of natural superdisintegrants, nanoparticle incorporation, and 3D printing technology are highlighted for their potential to further optimize Amlodipine Besylate FDTs. The article also addresses formulation challenges and future perspectives, emphasizing the role of innovative excipients and technologies in the development of effective, patient-friendly fast disintegrating tablets for cardiovascular therapy.

Keywords

Fast disintegrating tablets, superdisintegrants, Amlodipine Besylate

Introduction

Amlodipine besylate (Figure 1) is a calcium channel blocker or slow channel blocker or long-acting dihydropyridine derivative. Its mechanism of action involves inhibition of transmembrane influx of calcium through L-type calcium channels. In vascular smooth muscle, amlodipine decreases the influx of calcium ions which in turn decreases intracellular calcium concentration and causes vasodilatation leading to decrease in peripheral vascular resistance. In the heart, decreased calcium ions reduce force of contraction as well as decrease of calcium available for release in the action potential, thereby reducing heart rate [7]. Due to a prolonged half-life, due effect also persists even after the drug is withdrawn. Amlodipine is used in the treatment of hypertension, angina pectoris, including vasospastic angina and angina secondary to atherosclerosis, and coronary artery disease [8]. Amlodipine is generally preferred for oral dosage forms. Conventional tablets have definite demerits because many patients find difficulty in swallowing conventional dosage forms like tablets and capsules. Tablets being solid dosage forms require a minimum quantity of water for swallowing. Many patients also find difficulty in swallowing tablets and capsules, which may lead to ineffective therapy. Disintegration of the tablet forms into particulate matter and subsequent dissolution in saliva is time-consuming and becomes a barrier for the action of the drug. Regarding patient complaint, children's compliance can further be a problem in misleading, unintentional mechanism of delivery. Elderly patients, those who are either bedridden or have been limited to conditions such as stroke or unconsciousness, or have psychiatric problems, such as schizophrenia, find it difficult to swallow tablets [9]. A rapid onset of action of drugs is required for immediate pain relief. There exist many systems which provide controlled release of drugs for long action but these are not suitable for the acute attack. Fast dissolving dosage forms (FDDFs) or rapidly disintegrating dosage forms (RDDFs) disperse, disintegrate, and dissolve quickly in the oral cavity without the presence of water and provide better bioavailability and clinical efficacy than the currently available market formulations as conventional dosage forms do not dissolve rapidly and do not show its action [10].

Advantages of Fast Disintegrating Tablets (FDTs) for Hypertensive Patients

1. Improved Patient Compliance: Hypertension often requires long-term medication, and FDTs make it easier for patients to adhere to their treatment. Since FDTs rapidly disintegrate in the mouth without water, they are convenient for patients who have difficulty swallowing conventional tablets, such as elderly or those with dysphagia.
2. Rapid Onset of Action: FDTs disintegrate quickly in the oral cavity, allowing the drug to be absorbed faster either through the oral mucosa or after rapid dissolution and swallowing. This can lead to a quicker therapeutic effect, which is beneficial in managing blood pressure fluctuations.
3. Ease of Administration: The ease of taking medication without water makes FDTs ideal for hypertensive patients who are often on multiple drugs and may find it cumbersome to carry water or remember to take tablets properly.
4. Enhanced Bioavailability: Some FDT formulations can bypass the first-pass metabolism via absorption in the oral mucosa, improving the bioavailability of drugs like Amlodipine Besylate, which may enhance efficacy at lower doses.
5. Better Palatability: Bitter taste masking in FDTs enhances patient acceptance, which is crucial for chronic conditions like hypertension where lifelong therapy is required.
6. Convenient for On-the-Go Use: Hypertensive patients can take FDTs anytime and anywhere without the need for water, which improves convenience and flexibility in daily life.
7. Reduced Risk of Choking: Particularly important for elderly hypertensive patients, FDTs reduce choking hazards associated with swallowing large conventional tablets [11].

Amlodipine Besylate: Physicochemical and Biopharmaceutical Considerations

Fast dissolving dosage forms refer to tablets or oral films that disintegrate, dissolve or suspend in saliva in the mouth, delivering the drug to the systemic circulation without swallowing. The most popular formulation is the orally disintegrating tablet (ODT). This dosage form is useful for patients that have difficulty swallowing a conventional tablet or capsule leading to ineffective therapy. These patients include pediatric, geriatric and bedridden patients. The idea of formulating fast dissolving tablets emerged owing to the increase in new products which need to be administered orally in a liquid form or owing to the increase in the share of the swallowing impaired patients of the normal population. Growth in the global market for fast dissolving drugs form designs specifically targeting pediatric, geriatric and bedridden patients from all over the world. It is also reported that in one of the research studies involving 75 150 mg weight normal healthy volunteers, about 1/3rd of the adults exhibited difficulty in swallowing water-soluble tablet formulations. The global oral solid dose forms market is expected to grow from USD 246.1 billion in 2021 to USD 352.4 billion in 2027, Asian markets being the fastest growing in this segment with North America being the largest market share holder [12].  Presently, a relatively new class of drugs, which dissolve in the mouth without the need of any water, is drawing the attention of researchers and scientists. These drugs are known as fast dissolving drugs and the dosage forms are known as fast dissolving dosage forms. Fast dissolving is a term used for a newly developed class of formulations that disintegrates, dissolves or suspends in saliva in the mouth, resulting in enzymatic degradation of the active agent and subsequently its absorption in the systemic circulation [13]. Amongst them, the fast-dissolving tablets are the most popular formulations for delivering drugs through the oral route. The fast-dissolving tablets are normally compressed tablets containing super disintegrants that upon contact with saliva, quickly disintegrate and dissolve to release a drug for bioavailability.

Solubility and stability profile

Amlodipine besylate was obtained from a supplier in Mumbai. Mannitol was obtained from another supplier in Mumbai. All other excipients used were of pharmaceutical grades. Fast dissolving tablet of Amlodipine Besylate were prepared with varying concentration of super disintegrants like Crospovidone, Croscarmellose Sodium & Sodium Starch Glycolate. Preparation of fast disintegrating tablets by wet granulation method. The physical parameters like hardness, weight variation, friability, and disintegration time were evaluated for the prepared tablets. Compatibility studies were performed using FTIR spectrophotometer. In Vitro release studies were performed in pH 6.8 Phosphate buffer for 24 hrs. The results of the spectrophotometric determination of amlodipine besylate were linear within the 10-40µg/ml. The limit of detection and limit of quantitation was found to be 0.294µg/ml and 0.894µg/ml respectively. The solubility of amlodipine besylate was screened in different solvents. All the tablets passed the thickness, content uniformity, hardness, and friability. The disintegration time of all the formulations was found to be less than 30 sec, which is the official requirement of a fast-dissolving tablet. Stability study of optimized formulation was carried out and was found to be stable [14].  It is concluded that deliver faster dissolution and disintegration profiles for human health and safety response of drugs. With the limitation of one or few drugs selected for formulation development and they are able to provide the quality clinical response in advance for the age group of 2 to 50. The released drug was estimated based on the calibration plot which was linear from 0 to 250 µg/ml of drug. Hence drug, polymer ratios were standardized for continued evaluation for FDT. The blend showed good flow properties as the angle of repose, Carr’s index and Hausner’s ratio were found to be 26.29, 7.4, 1.075 respectively, which was ensured for good flow properties. The pre-compression and post-compression evaluation of formulation 1 to formulation 9 was carried out. Both the hardness and thickness of the tablets were in the limit. The friability of the compression tablet was lower than 1% indicating good mechanical resistance. The estimations for weight variation showed that all the formulations are within the acceptable limits and passed the test. The percentage drug content uniformity was within limits, indicating the uniformity of drug distribution in all the tablets. The tablets completely disintegrated within 75 sec where the presence of super disintegrants Crosspovidone reduced the disintegration time of the tablet significantly compared to the other formulations [15]. 

Challenges in formulation

Formulating fast disintegrating tablets (FDTs) poses several challenges, including balancing mechanical strength with rapid disintegration since tablets must be sturdy enough for handling yet dissolve quickly in the mouth. Taste masking of bitter drugs is difficult without affecting disintegration or drug release. Selecting suitable excipients that promote fast disintegration while maintaining tablet integrity is complex, and dose limitations restrict formulation of high-dose drugs due to size and mouthfeel. Additionally, FDTs are often moisture-sensitive, requiring careful packaging to ensure stability. Manufacturing these tablets involves specialized, costly technologies, and ensuring uniform drug distribution in small tablets is critical to maintain dose accuracy. Finally, achieving a pleasant mouthfeel without grittiness while preserving rapid disintegration adds to the formulation complexity [16].

Formulation Strategies for Amlodipine Besylate FDTs

Amlodipine besylate (10 mg), sodium starch glycolate (5, 10, 15 mg), starch potato (4, 8, 12 mg), and camphor (5, 10, 15 mg) were accurately weighed. Sodium starch glycolate, starch potato, and camphor were mixed separately and mixed with amlodipine besylate in a mortar. Then, talc was added as a lubricant. Tablets were compressed using 12 mm round flat punches on an 8 Station tablet machine. The evaluation of tablets was done for hardness, friability, disintegration time, and in vitro release study [17].

Direct Compression Method

Direct compression method is one of the most popular and widely utilized processes for the manufacture of tablets in pharmaceutical sectors. Fast dissolving tablets of Amlodipine Besylate were prepared by direct compression method using superdisintegrants. The formulation contained Avicel PH 102, Mannitol, SSG, and NaHCO3 in different concentrations and evaluated for pre-compression and post-compression parameters [18]. The drug excipients were mixed uniformly in a mortar. The lubricants were passed through sieve No. 60 and mixed well with the drug and excipients uniformly on a mortar. The tablets were compressed using hardness. The hardness of Amlodipine Besylate was determined using a tablet hardness tester. Ten tablets were randomly selected from each formulation and taken into the tester. The hardness of each tablet was determined in kg/cm2 and the average hardness was calculated. The thickness of tablet A and B was determined, and 5 whole tablets were selected at random and arranged in a stack. The thickness was measured using a microcaliper at the center of the tablet in the tablet standing position. The values would be average of five thicknesses and the standard deviation was calculated. The variation in tablet weight was determined by weighing 20 tablets individually and collectively and average weight was determined. Weight variation was calculated as follows. The tablet friability was determined using a Roche friabilator. 20 tablets were weighed and placed in the friabilator drum. The friabilator was operated for 100 counts. The tablets were dusted and reweighed. The percentage friability was calculated. The thickness of tablets was assessed using a Vernier caliper. The thickness of 5 tablets was determined individually and averaged and S.D was calculated. The disintegration test was performed using disintegration test apparatus, a USP apparatus. Amlodipine Besylate tablet disintegration test was done in distilled water (pH 7.4) of 37±0.50C. The disintegration time was determined in minutes by recording the time, mucoadhesion time, and percentage multiply by six scored by 2 if it got Stuck to the Flakes and one if its literacy got detached, and evaluated.

Lyophilization

Lyophilization of 1-hydroxy-2-pyrrolidinone and Amlodipine Besylate was carried out on the samples, which had been successfully compressed. A lyophilizer was used. The freeze-dried formulations were evaluated for the reconstitution time, drug content, water absorption ratio, and wetting time. The optimum coating levels were found to be used in the formulations (70mg). After determination of the optimum level of drug, coating material, and carrier for precipitant, a 72 run factorial design was applied on course size. The optimum level of effective variables determined by using software was coated hard gelatin capsules with 70mg, 30mg, and 0.2mg respectively. Fourier transform infrared spectroscopy was used to study the interaction between drug and excipients. There was no interaction of amlodipine besylate with other excipients in the formulation. The formulation having the excipient, Hydroxy propyl methylcellulose (E5) controlled the release of 100.92% up to a period of 12 hours. The formulation was digested to about 99.50% in simulated intestinal fluid containing phosphate buffer pH 6.8 and 33.90% in simulated gastric juice containing 0.1NHcl. In vitro release kinetics showed that the mode of drug release diffusion from the pellets follows first-order kinetics and the drug release mechanism is by non-fickian diffusion. The optimized formulation clusters were sealed in blister packs and stored at 25 ± 2 ⁰C for 3 months. The formulation was found to be stable, as there were no notable changes in the physicochemical properties. The optimized formulation was found to contain an 81.40% release of drug in 7 hours.

Sublimation

The plaster molding technique was employed for the fabrication of fast disintegrating tablets, and a full-factorial design was employed to study the effects of the concentration of potato starch, camphor, and sodium starch glycolate on the formulations for the quality control parameters. In order to facilitate drug release, the sublimable agent "camphor," along with other excipients, played a critical part in the preparation of FDT employing a modified plaster of Paris method. Drug-polymer interactions were examined using Fourier transformed infrared spectroscopy (FTIR). The dissolution studies of FDT demonstrated that formulation F6 was the best formulation, which was prepared at a ratio of potato starch, sodium starch glycolate, and camphor at 0.5:0.5:5. Comparing the lipophilicity of the bulk drug molecule and the marketed tablet, the assay determination revealed some degradation of the drug in the marketed tablet but not in the FDT. In vivo assessment of the disintegration and dissolution of the prepared formulation was performed using healthy dogs and market tablets for comparison. The results demonstrated that the disintegrating time and onset of action were considerably improved relative to the marketed formulations. The content uniformity and stability investigation also revealed that the FDT stored at 4’s and 8’ had no appreciable changes when contrasted to the marketed product. It was finally concluded that the sublimation method could be used to formulate and prepare modified dosage forms that release two medications, with a solid dose weight of up to 250 mg.

Spray Drying

The drug is monitored as a function of time using the UV spectrophotometer. This is used to find the ability of selected formulation to release the drug. For this, 10 mg of drug from each formulation is dissolved in 100 ml of buffer solution. 10 ml of the solution is taken at pre-determined time interval. 10 ml of methanol is added to 10 ml of buffer solution and then the solution is analyzed UV spectrophotometrically at 354 nm against buffer as blank [17-19]. The scanning range is decided on the basis of solubility and wavelength of maximum absorbance of drug in buffer. The retention time for these peaks indicates the time until the drug stays in the column. The parameters that affect the retention time of the drug are decided first. These parameters include the mobile phase, flow rate and the column temperature. Among these parameters, the effect of the mobile phase was studied more extensively in an attempt to optimize the separation. The ratio of the buffer to methanol is varied primarily for gradient elution. The solubility of the drug in any organic solvent exerts a dramatic effect on retention time and peak shape. The buffer used in this work should be methanol and potassium dihydrogen orthophosphate having a pH of 7.2. The diluents should be recently freshly prepared to ensure that the buffer remains stable. Any fluctuations in the mobile phase or column temperature can lead to substantial variation in retention time and may increase the baseline noise. Solvents should be accompanied by a minimum of 5 repeats before the run. The column should be allowed to equilibrate for not less than 30 minutes before running on any injection. The minimum maintenance should include a daily system suitability test, which should be embedded in the method run. It involves injecting standards of known concentration and comparing by a set of decision rules (limit 5-10%, drift of >20%) with earlier similar data to ensure that no important variation is present. One of the greatest disadvantages is that UV detectors can only detect anomalies that are associated with solutes that exhibit a UV absorption. As many compounds do not have a chromophore, only a limited range of analytes can be detected [19,20].

Superdisintegrants

In this research to encounter the problems such as palatability, swallowing difficulties due to multiple diseases of patients and geriatric patients without chewing a tablet, the effort to formulate fast disintegrating tablets of olopamidhydrochloride was made with an incorporation of superdisintegrants like crospovidone, croscarmellose sodium and sodium starch glycolate for rapid disintegration of the tablet. Simple direct compression method was adapted to formulate fast disintegrating tablets of olopamidhydrochloride. All the powdered blends of olopamidhydrochloride containing varying concentration of avicel pH 101, mannitol, talc and magnesium stearate were characterized with respect to pre-compression parameters and were also subjected for post compression evaluation of the tablets [21]. Fast disintegrating tablets are user friendly dosage form for those who wish to take their medicine anytime and anywhere. The aim of this study is to formulate fast disintegrating tablets of olopamid hydrochloride using superdisintegrants by direct compression method. The rapid dispersion was achieved successfully within 10 seconds. Stability studies were carried out according to ICH guidelines, formulation were chemically stable and did not show any significant change in physical appearance, disintegration time and assay during the study. They are quite comfortable for administration without moistening and showed good taste masking of olopamidhydrochloride. Fast dissolving tablets are user friendly dosage form for those who wish to take their medicine anytime and anywhere. Fast disintegrating tablets of olopamidhydrochloride were prepared using superdisintegrants along with other excipients by direct compression method. Formulation f4 was considered as the best formulation in all aspects. Formulation f4 was successful in the objective to produce fast disintegrating tablets which was capable of rapid disintegration and in vitro dissolution in oral cavity of ory dose formulation. Super disintegrants expand in an aqueous environment, initiate disintegration and result in rapid release of the medicament [22].

Crospovidone, Croscarmellose sodium and Sodium starch glycolate

In recent years, many pharmaceutical companies and research institutions have placed more emphasis on the development of non-conventional dosage forms such as fast dissolving dosage forms. Fast dissolving tablet dispersions may deliver drug within seconds to patients who are unable to swallow traditional pills and capsules. Fast dissolving drug delivery systems have gained popularity over conventional dosage forms because of their ability to dissolve quickly in salivary fluids, making them beneficial for elderly and pediatric patients, as well as people who may be reticent to use conventional dosage forms. The oral cavity is also a location in which systemic absorption through the tissues lining the mouth, gingival, oropharynx, and pharynx can take place. As a result, using fast-dissolving tablet systems containing a drug with low aqueous solubility may lower the time to the onset of action [23]. As a result, the breadth of potential applications for fast dissolving systems is increasing. Except for the use of well-established drugs, the chance of success and the research & development time in the formulation of new drug delivery systems are generally increased and greatly lengthened. Fast dissolving tablets are a new, emerging drug delivery system that absorbs rapidly in the mouth and produces an effect within 90 seconds. Tablets in the traditional sense that would dissolve in the mouth and then swallow with a glass of water are no longer enough. Recently, fast dissolving dosage forms have become popular. In oral drug delivery forms, this is a new technique for mouth dissolving dosage forms. Many patients dislike swallowing tablets/capsules, especially with water, due to fear of choking. In the case of geriatric patients, retired patients, or children, difficulties may arise. It causes non-compliance. Those people also find it a time-consuming procedure which may have an effect on the patent action of the medications. Antacid medicines or any over-the-counter medicines that ease pain or discomfort are wanted by patients experiencing heartburn, indigestion, or headache; they may want something to take quickly and discreetly [24].  This formulation study deals with cuddle Jace type fast disintegrating tablets of Amlodipine Besylate. Amlodipine Besylate is a calcium channel inhibitor used to treat on hypertension and angina. An orally disintegrating tablet is a dosage form that contains a medicinal substance or active ingredient which disintegrates rapidly, usually within 60 seconds, when placed upon the tongue. Fast Dissolving Tablets are generally formulated with super disintegrants, as their name implies, that are particularly effective at promoting the rapid breakup of the tablet in the oral cavity. Amlodipine is a calcium channel blocker, which is used for treating hypertension and other conditions in which it is desirable to lower blood pressure. It can be used either alone or together with a second drug to improve blood pressure reduction [25]. 

Role of Excipients in FDTs

Choice of drug molecule: Amlodipine besylate, an anti-hypertensive drug of category dihydropyridine derivative, is a long-acting Ca2+ channel blocker widely used for the treatment of high blood pressure and chronic stable angina. Amlodipine besylate is highly soluble in water and alcohol and poorly soluble in acetone. Fast disintegrating tablets of amlodipine besylate were prepared by sublimation method using agents like camphor and ammonium bicarbonate. The excipients were selected by conducting various compatibility studies viz. studies and based on the solubility profile of the drug. studies revealed that there is no drug-excipient interaction.

Formulation of FDTs: Fast disintegrating tablets of amlodipine besylate were prepared using sublimation method. The powders were prepared by mixing the drug, excipients and subliming agent in 4:1 ratio and were all subjected to pre-formulation studies. All the powders were evaluated for angle of repose, bulk density, tapped density, compressibility index and drug content. The results of the studies were within acceptable limits. Direct compression of FDTs using sublimated powder mixtures yields FDT using 15% compile as a subliming agent. FDTs of batch 4 and batch 5 were sent to stability studies as they showed rapid drug release characteristics and lesser disintegration time compared to all other formulations. Batch 4 and batch 5 formulations had optimum concentration of subliming agent to produce well defined porosity in tablets which resulted in increased surface area. The proper selection of super disintegrating agents also plays vital role in enhancing disintegration [26].

Evaluation of FDTs: Evaluation of the prepared tablets was done for various parameters which revealed that the tablets possess good pharmacopeial characteristics and were found to be smooth and non-sticky. The drug content was uniform and within the limits. In vitro disintegrating time was determined in 900ml of distilled water using solution for visualization purpose. The disintegration time was found to be 25-50 seconds. The in vitro dissolution studies were performed using apparatus. The results indicated that there was an increase in the rate and extent of drug dissolution for optimized formulation when compared to the batch containing different concentrations of starch or superdisintegrating agents. In vivo evaluations such as palatability study were conducted. From the present findings, it may be concluded that the drug can be formulated successfully into fast disintegrating tablets by using sublimation technique [27]. 

Superdisintegrants

Superdisintegrants are the key excipients involved in the formulation of fast disintegrating tablets. They facilitate rapid breakup of tablets when they come in contact with aqueous media, letting the medicament disperse readily in solution. Sodium starch glycolate, cross carmellose sodium and microcrystalline cellulose are important super disintegrants. Sodium starch glycolate, a commonly used super disintegrant, is derived from starch by the process of etherification. It is a white, pale cream or pink colored, odorless powder with neutral to slightly acidic pH and is freely soluble in sodium hydroxide and slightly soluble in alcohol and ether. It swells in water to a maximum of 7-8 times its weight without any change of state. Cross carmellose sodium is a cross-linked sodium carboxymethyl cellulose that is mainly used as super disintegrants in formulation of tablets and capsules. Being swellable, it absorbs water and causes the tablet to swell. For cross carmellose sodium swelling approximately two seconds of time is taken and hence it helps in rapid disintegration of tablet. Generally cellulose takes a long time to swell because of its crystalline structure but by adding cros link it enhances the solubility [28]. Crosscarmellose sodium is an odorless, white or off-white, crystalline powder. It is hygroscopic in nature. Micro crystalline cellulose is used as a disintegrating agent as it promotes hard tablets with plethora of porosity. Bioadhesion which is a rare property of excipients can be denoted using micro crystalline cellulose. Micro crystalline cellulose is a white to off-white powder having porous structure. It is odourless and tasteless in nature. It is insoluble in water, alkali and organic solvents. Micro crystalline cellulose was found to be used in the concentration range of 0% to 15%.

Fillers and binders

The flowability of the powder blend was determined using an analyzer. The nature of the prepared powder blend was wonderful, as detected by a flowability test done with a Glockler powder flow tester. The low bulk density shows that there is poor inter particle attraction between them and the powder does not flow well. In the present study this is due to the use of microcrystalline cellulose, which acts as a disintegrant and gives a higher bulk density to the critical formulation. The compressed tablets were evaluated for weight variation, hardness, friability, thickness and diameter as per the pharmacopoeial standards. The weight variation for all the formulations complied with the pharmacopoeial limits. The mean hardness of the formulations was compared statistically not significant at (P < 0.05). The formulations were lower in hardness, friability, thickness and diameter. In-vitro disintegrating time of the formulations were estimated using a disintegration apparatus. In-vitro release of the drug ergeted from the prepared formulations was determined using a USP XXIV type II apparatus. The obtained data was applied to various kinetic equations to understand the release mechanism. The formulations L10, L9 and L8 were selected for the stability studies, which were packed in sealable aluminum foil pouch and subjected to the stability testing at 40° + 2° and 75% + 5% RH for a period of 2 months. At periodic intervals the tablets were analyzed for hardness, drug content, weight loss and in-vitro drug release characteristics. Fast disintegrating dosage forms are defined as those dosage forms which are converted into a liquid form when put in mouth within a matter of seconds or disintegrated, dissolved or suspended by saliva in the mouth. Fast dissolving tablets/thin films/buccal tablets have been of considerable interest for two decades. It is a recent addition to the drug delivery systems and prior to the introduction of these, the patients who may have difficulty in swallowing conventional tablets or capsules leading to ineffective therapy. Amlodipine besylate a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Hypertension is a key contributor to morbidity and mortality throughout the world; an increase in cardiovascular diseases and high blood pressure is particularly evident in the developing countries. The present study aimed at exploring the potential for improving the bioavailability of amlodipine besylate by solid dispersion approach using PEG6000 and polyvinyl pyrolidine as excipients and rapid absorbable tablets using gas forming agents paired with conventional superdisintegrants optimizing the level of each by 2 3 factorial design [29-31]. 

Flavoring and sweetening agents

The flavoring agent used in this formulation was strawberry and 2% was chosen as the optimum level of flavoring agent necessary to mask the bitterness of amlodipine besylate effective formulation. The sweetening agent sucrose was selected as the optimum level due to the superior property over other sweetening agents. In the present formulation, 0.18 g% sodium saccharine was chosen as the optimum level of sweetening agent. The optimum level of sweetening and flavoring agent hence two required additives among those tested were selected on the basis of sensory evaluation test. The compression cuffs were used for the manufacture of non-blue spherical sugar-coated tablet beads. The yellow tablets were formed using pre-coated sugar beads kept on hot plate over which cores were coated with acacia batches. The elastic modulus indicated either soft or hard paints. The lower the Young’s modulus the greater the flexibility of the paint. This demonstrated that the presence of the additive sugar glass beads rendered tablets less brittle. Other excipients were added for appropriate amounts to achieve the required moisture permeability of the tablets. The post-compression parameters like thickness, hardness, friability and weight variation were studied. To study the association of polymer and drug, tablets of fast disintegrating and wax-coated tablet were prepared using optimum level of active ingredients. Post-compression parameters were checked as above and some of them were found to be improved. They were suitable for the disintegration and dissolution test. The X-ray diffraction of the drug tablets resolved in less sharp peaks. The peaks again showed the amorphous nature of the drug. The in vitro dissolution study data was obtained. The wax-coated tablet showed a sustained release profile but the time needed was more this is a slow action. The disintegration time was cure faster in the case of marketed tablet but the measured value was very low which could not be measured since it was completely and instantaneously dissolved in the PBS using a UV spectrophotometer. The sustained release showed first order, Weibull, and Peppas kinetics with a good correlation coefficient [32]. 

Lubricants

"Stearic acid, glyceryl monostearate, and their combination in equal ratios were used as lubricants. The lubricating agents were sieved through 40 mesh and mixed with tablet blend in a mortar to prepare uniform dispersion." The bulky solid lubricants in excess quantity do not get dispersed uniformly and thus cause the formation of weak tablets. In the case of magnesium stearate, the solid lubricant is moist compared to the tablet blend, coating it during blending and forming a dry rigid ball. Excess lubrication of the blend was ruled out because the tablets formed at all concentrations were of similar hardness, and lowering the concentration of lubricant did not increase the hardness of the tablets. More lubrication leads to sluggish punch movement or machine stoppage, but only one tablet failed in the tablet machine. Nonetheless, it was decided to refer to F2 as the optimum formulation. The mixture was permitted to stand for 2 h for the lubricant to act before commencing compression. All the formulations were compressed using the Cadmach tablet punching machine using sixteen-station cylindrical punches with a diameter of 8.8 mm. The parameters, such as compression strength, tablet weight uniformity, and drug content were determined to be satisfactory for all produced tablets. These studies provided insight into the importance of the disintegrant and the evacuation of the sublimed solid from the tablet [33].

Evaluation Parameters of FDTs

Pre-compression Evaluation

Angle of repose, bulk/tapped density, compressibility index

The angles of repose with respect to Ishida were determined and average values were calculated. The bulk and tapped densities of the samples were measured and recorded. The compressibility index (Carr's index) was calculated using the inbuilt equation which was used to calculate flow properties. The flowability was determined using Hi - Shear Mixer as per the general procedure. Angle of repose, bulk density, tapped density, carr's index, and Hausner's ratio were evaluated. The flow properties were evaluated for the blends. The angle of repose of the granules was found to be 30? to 34?, indicating good flow property. The bulk density of the granules was found to be between 0.44 and 0.48 gm/cm3, indicating good flowability. The tapped density of the granules was found to be between 0.40 and 0.51 gm/cm3. The Carr’s index of the granules was found to be between 16.12 and 20.73, which indicates that the granules possessing fair to good compressibility. The Hausner’s ratio was found to be between 1.26 and 1.30, which indicates that the granules have a good flow property [34].

Post-compression Evaluation

Tablet Size

The diameter of the easiest tablet to swallow has been reported to be 7-8 mm, while tablets that are easily handled have diameters greater than 8 mm. The size of tablets that can be formulated has to be considered in conjunction with how the tablet can be expected to be administered. Tablets that are dry, smooth, and well lubricated easily slide down the esophagus. If the angle between its major and minor axes is less than 80° and the difference between the normal and major body diameter is less than two-thirds of the normal diameter, a tablet is obstructed in the esophagus. Various methods can be utilized to determine whether the tablet has drifted into the trachea because the shape and bulk density make these tablets different from those that would fit in the bronchial tubes. The problem of obtaining satisfactory dose uniformity for a range of drugs and dosages.

Determination of Weight Variation: 20 tablets were weighed individually and average weight noted. The percentage deviation was calculated using the formula in. Drug content uniformity testing was performed by taking 10 tablets from different places and tested with respect to an equivalent weight of Amlodipine besylate.

Hardness Test: The hardness of the tablets was determined using a scientist hardness tester. It is expressed in kg/cm². Three tablets were selected randomly from each formulation and the hardness was tested.

Friability Test: The friability of the tablets was determined using Roche friabilator. Pre-weighed tablets were placed in the friabilator, which was then operated for 100 revolutions. Tablets were dusted and reweighed. The % Friability can be calculated by.

Disintegration Test: Disintegration time was tested by using a disintegration test apparatus. Tablets were placed in each tube and time required for entire disintegration of the tablet into particles was measured. Six tablets from each formulation were tested.

Dissolution Test: The dissolution of amlodipine besylate tablets was carried out using USP XXIV type I dissolution apparatus (basket type) in 900 ml of 1 N HCL maintained at 37±10C and 100 rpm. At regular intervals of time 10 ml of the sample was withdrawn and the samples were analyzed using UV spectroscopy at 238 nm against the blank dissolution medium. 5 ml of fresh medium was added to maintain the volume.

Assay of Amlodipine Besylate: Preparation of stock and working standards of Amlodipine besylate. Preparation of sample solution for assay.

Tablet hardness and friability

The tablet properties such as hardness and friability were determined for the prepared tablets. The Tablet Crushing Load was determined using a device which measured the force required to break a tablet into pieces by compression. This device essentially consisted of a 2-chamber pneumatic system with a capsule holder in one chamber and a pressure gauge in another. The force required for the tablet to get crushed was expressed in Kg. The strength of tablet is expressed as tensile strength (Kg/cm²). The tensile strength of the tablets was calculated using the following equation 1: Where β = Tensile Strength (Kg/cm 2); F = Breaking Load (Kg); D = Diameter of tablets (cm); T = Thickness of a tablet (cm) and Friability = It is defined as the measure of tablet strength. Roche friabilator was used to determine friability. Friability = (w 1 - w 2) / w 1 × 100. Where w 1 = weight of 20 tablets before test and w 2 = weight of 20 tablets after test. Pre-weighed 20 tablets were placed in the friabilator, which was then operated for 100 revolutions. Tablets were dusted and reweighed.

Disintegration time

The disintegration time of all formulations was determined and the results are shown in Table 5. On increasing the concentration of Starch potato by keeping the concentration of Camphor and SSG constant at 100 mg and 50 mg respectively, the mean disintegration time of the formulations was found to decrease from 38.8 sec to 20.5 sec. The mean disintegration time of formulations F6, F7, F8 was only 35.5 sec, 30.35 sec and 25.1 sec. The three formulations were found to possess high efficacy as they showed fast disintegration time. Hence the formulations were further subjected to evaluation of other parameters. In case of the formulation F1 to F5 in which the concentration of Camphor was increased from 20 mg to 100 mg keeping the concentration of Starch potato and SSG fixed at 100 mg and 50 mg respectively the mean disintegration time was just 42.38 sec to 31 sec. It was found that the increase in amount of effervescent agent from 20 mg to 100 mg increased the disintegration time. The disintegration time of the formulations made using 50 mg Sodium Starch Glycolate, 100 mg Starch potato and 20 mg of Camphor was found to be 22.5 sec. The disintegration time of the formulations F3 with 20 mg of Camphor was about 32 sec. Hence Formulation F1 with Camphor 20 mg, Starch potato 100 mg, and SSG 50 mg possessed the negligible disintegration time. Formulation F1 with a combination of Camphor 20 mg, Starch potato 100 mg, and SSG 50 mg was selected as the optimized formulation for evaluating the post compression parameters. The disintegration time of other formulations was found to be more than 50 sec; hence they were not selected for the post compression evaluation [35-38].

Wetting time and water absorption ratio

Amlodipine besylate is an antihypertensive agent used in oral therapy for the treatment of hypertension. High water solubility and high permeability were obtained with a BCS classification. Developed orodispersible tablets of amlodipine besylate employing a combination of amlodipine besylate and a coprocessed excipient super disintegrant. The physical characteristics, precompression, and postcompression characteristics of the tablets were evaluated. The rate of disintegration and dissolution was improved as compared to plain amlodipine besylate and with the addition of SSG. With optimization of the ratio of super disintegrants and amlodipine besylate in the coprocessing method results in improved disintegration and dissolution rate of the drug [39].  Orodispersible tablets of ambroxol need to hasten the disintegration of the tablet in the oral cavity on the tongue to give fast release. The main focus of this study was the formulation of Amla fast dissolving tablets with an emphasis on taste masking of the active drug (Amla) so that the product would be acceptable for paediatric usage. Vaginal tablets of Amlodipine besylate were formulated with coprocessed superdisintegrant through the direct compression method. Optimization was done using central composite design tool by keeping the disintegration time and friability as critical quality attributes (CQAs). To obtain the rapid disintegration of tablets in wet media conditions, co-processing of excipients was done using different ratios of cross-carmellose sodium and microcrystalline cellulose (MCC). Wetting time is affected by the type of co-processed excipients Ratio of co-processed excipients. Among all the formulations, F3 formulation is the optimized formulation having 1:5 ratios of Crosscarmellose sodium and Microcrystalline cellulose (MCC), a combination of co-processed excipients resulted in the sustained release of Amlodipine besylate in 12 hours.

In-vitro dissolution studies

In-vitro dissolution studies of amlodipine besylate were performed for 20 minutes using a basket type dissolution apparatus, wherein 900 ml of 0.1N HCl (pH 1.2) was used as dissolution medium and at 37±0.5°C as a temperature. Samples were withdrawn after every 5 minutes and the same was filtered and analyzed at 239 nm using a UV-visible spectrophotometer. A blank dissolution medium was used to prepare the standard solution and to carry on the analysis. The same conditions were maintained for working standard and standard graphs were plotted between concentration (µg/ml) and absorbance, and the regression equations were derived. From the % release data, comparing with the standard curve developed was used to calculate the % drug release. All the % dissolution release data was reported in mean + SD (N=3). All the samples were run in triplicate for confirmation of their validity. In-vitro dissolution data was analyzed through software to carry on the estimation of model fitting. The goodness of fit was carried out using ANOVA. The fast-disintegrating tablets of amlodipine besylate were successfully prepared using sublimation technique. The FTIR and DTA studies revealed that there was no interaction between drug and excipients used. Among all the formulations, F6 was found to be the best formulation with hardness of 3.6 kg/cm2, thickness 4.9 mm, disintegration time of 14 seconds, wetting time of 17 seconds, friability of 0.37%. The drug release studies showed that 98.80% drug was released within 10 minutes from F4 formulation containing SSG 4% w/w as super disintegrant. The formulation was found to follow Higuchi model of drug release kinetics and non-fickian diffusion mechanism of release. To conclude, the fast-disintegrating tablets of amlodipine besylate were successfully prepared with improved disintegration and dissolution characteristics suitable for various geriatric applications.

Drug content uniformity

The drug content uniformity test was performed on the finished formulations by using UV spectrophotometer. The assay of Amlodipine besylate was performed using modified method described in the official monograph. The tablets were crushed and weighed and it was accurately weighed equivalent to 10 mg of Amlodipine besylate was transferred to a 100 ml volumetric flask containing 30 ml of 6.8 buffer and sonicated for 10 min and volume made up to 100 ml with the same buffer solution. The sample was filtered through a whatman filter paper and the first few milliliters was discarded. 10 ml of the filtrate was diluted to 100 ml with 6.8 buffer. The absorbance was measured at 359 nm [40]. Ten tablets were randomly selected from each formulation and they were analyzed in order to determine the drug content. The drug content was calculated using the standard curve data and the results of drug content were satisfactory. This indicates with in the limit of 90 - 110% drug content uniformity. Amlodipine besylate has a λmax at 359 nm in 6.8 buffer. The calibration curve was constructed by analyzing the solutions of 10 to 60 µg/ml concentration. The absorbance at 359 nm was measured and the linear regression plot was constructed with concentration on x - axis and absorbance on y - axis. The linear regression equations were obtained Y = 0.0266 X for amlodipine besylate with an intercept of -0.0242 and a correlation coefficient of 0.998 [41]. 

Stability studies (as per ICH guidelines)

Before initiating stability study, the optimized formulation was subjected to preliminary stability studies, according to ICH guidelines. The tablets were stored in airtight containers and kept at 40^oC temperature at 75 % RH using a stability chamber. At 0, 30 days, 60 days and 90 days intervals tablets were evaluated for physical appearance, drug content, disintegration time, and in vitro drug release. Physical appearance: The tablets were evaluated visually for color, shape, surface texture, and any defect or roughness at 0, 30, 60, 90 days and no significant changes were found. Drug content: Amlodipine Besylate content in the tablets was estimated spectrophotometrically at the maximum wavelength of 237 nm using the UV- Spectrophotometer. At 0, 30, 60, 90 days, it was found to be 98 %, which is a satisfactory value. Disintegration time: The disintegration test was carried out as per IP method using a disintegration testing apparatus. Amlodipine besylate fast disintegrating tablets were subjected to disintegration studies at 0, 30, 60, 90 days. At the end of 90 days, the optimized formulation (F5) was found to be a disintegration time of 27 sec, which is satisfactory in spite of a slight increase in disintegration time. In vitro drug release: In vitro dissolution studies of amlodipine besylate fast disintegrating were studied against drug and marketed formulations. After 90 days, the release of formulation F5 showed a drug release above 98 %, which is satisfactory and indicated that there is no significant change in the drug release profile when compared with fresh tablets [41].

Recent Research and Comparative Studies

Mouth dissolving films of Amlodipine Besylate (AB-FDFs) were prepared by solvent casting technique. AB-FDFs of an adequate thickness, transparent, and smooth surface were developed. The bode aspects for all films with variable film formers were done. Solubility and saturation solubility studies were performed. 43.29 microgram/mL of rigorous solubility was noted. 80% of drug load was inside better dissolution. The preferred film at in-vivo experiment shows mode size group of 44.32 microm LS; the drug was biocompatible. The practicability index value of both AB-PDF and AB-FDFs was 1, indicating its water-soluble movie which was rapid disintegrating its film in <45 seconds. Short transport time was noted, readily traversing further than 25 minutes [42].  Smart materials, which most normatively scope overcome the limitations of conventional hydrogel carriers to better perform in biomedical applications in-vivo are also constantly emerging. Among these, chitosan, being responsive to multiple stimuli, is the most widely researched smart polysaccharide. Hydrogel-based scaffolds encompassing suitable drug and growth factors are engineerable to be smart using arrows, polysaccharides, and other polymers to overcome the limitations of drug delivery systems. The designed smart drug delivery systems showcase an on-demand drug release profile in physiological conditions without tedious off-target toxicity. More intelligent (bio-) compatibility and (bio-) degradation are achievable via the incorporation of natural hydrophilic polymers. To keep these overview objectives focused, real-time monitoring of medications is not included here.

Comparative effectiveness of different superdisintegrants

The superdisintegrants crospovidone, croscarmellose sodium, and sodium starch glycolate (SSG) were used to prepare tablets. Six formulations were prepared with different superdisintegrants and their concentrations fixed weighing of all ingredients, powder mixtures were prepared by mixing the accumulatively the polyvinyl pyrrolidine, and superdisintegrants. Mucina gum was used as a mucilage on which the tablets were prepared by the wet granulation method. Tablets were subjected to various evaluations like hardness, thickness, weight variation, disintegration time, and stability studies. Among the six formulations prepared formulation F6 showed good results in disintegration time. Dissolution studies showed controlled release up to 10 hours for the prepared formulations therefore it may be concluded that the formulated tablets are ideal candidates for sustained drug delivery of aceclofenac. Fast dissolving tablets of naproxen sodium were prepared by direct compression method using various superdisintegrants and evaluated. Sodium starch glycolate, crosscarmellose sodium, and treated agar were used as superdisintegrants. FT-IR spectra of pure drugs and excipients showed that there were no drug-excipient interactions. The displaced powder showed good free-flow properties. The blend tablet containing sodium starch glycolate along with other superdisintegrants showed rapid in vitro dispersion time (2.20 seconds). The blend containing sodium starch glycolate showed a better in vitro dispersion time than the remaining formulation. The blended powder and formulation F4 were selected for further studies. The tablets were evaluated for hardness, thickness, weight variation, friability, and disintegration time [43].

FUTURE PERSPECTIVES

Amlodipine Besylate is a poorly water-soluble drug. The formulations of some of the batches containing 10mg Amlodipine Besylate showed an optimum concentration of disintegrants. Batch F8 (10 mg Amlodipine Besylate and 1.5:3 ratio of HPMC K15M and Starch5), which was formulated using the Method-1 (direct compression) showed an optimum release of 98.5% & 97.89% within 10.5 minutes & 11.25 minutes respectively. The tablets were evaluated for weight variation, thickness, hardness, friability, disintegration time, wetting time, and in vitro drug release study. The weight variation study indicated that the weights of all the formulated tablets were within the limits. The hardness of the tablets was tested with the help of a Monsanto hardness tester and the resistance offered to the crushing strength was sufficient to withstand the rigors of transportation. Results of the friability test showed that the percentage of friability was less than the limits of a suitable tablet. Thus, the disintegrating agents used in the preparation of tablets were more effective and influenced the results of the disintegration time. Tablets containing Super disintegrants Na Starch Glycolate, and Cross Carmellose Sodium showed a rapid disintegration time. The results of the disintegration time of all the formulations were found to be in the range of 20-45 seconds. A formulation containing a higher concentration of crosscarmellose sodium (1.5%) showed optimum results, with disintegration time being 20 seconds. From this investigation, it can be concluded that AMLO can be successfully formulated into MDFs. All the MDFs prepared with HPMC E3, E5, E15, and MC as film formers possessed good physicomechanical and dissolution properties. The MDFs showed no change in the homogeneity, transparency, color, and smoothness properties even at the end of the 6-month time period (25?C/65% RH) when compared to initial properties and especially no crystallization of the AMLO was observed. These results are indicative of the stability of AMLO in MDFs. The developed AMLO MDFs may provide quick onset of action with improved oral bioavailability and enhanced patient compliance and therapeutic efficacy when compared to the current marketed formulations like IR and ODTs [44].

CONCLUSION

On the whole the amlodipine besylate fast disintegrating tablets were prepared by using lyophilized acacia gum. In this study on optimization parameters and evaluation methods were carried out as per the procedure discussed earlier. The tablets were evaluated for hardness, weight, thickness, friability, disintegration time and in vitro dissolution study. FTIR studies showed that no drug excipient interactions occurred in final formulation. The dissolution studies indicate that formulation F3 containing 1:2 ratio of drug and polymer showed EVG in 14 minutes with 81.2% drug release. The order of release was found to be first order. Stability studies were carried out for the F3 formulation and it was found that there was no significant change in hardness and disintegration time at refrigeration conditions and room temperature. Thus, it can be summarized that Preformulation studies of FDT was carried out with various excipients. The compatibility of drug with excipients was confirmed by IR spectral studies. Fast disintegrating tablets of amlodipine besylate were successfully prepared by lyophilization technique, which increases the solubility. The formulations were evaluated for different parameters like hardness, thickness, friability, disintegration time, in vitro dissolution and stability studies. The study was conducted to formulate and evaluate fast dissolving tablets of amlodipine besylate with different super disintegrates by using melt granulation techniques. All the formulations were evaluated for weight variation, hardness, thickness, friability, wetting time, water absorption ratio, disintegration time and In-vitro dissolution studies. The results of the study showed that formulation F10 containing crosspovidone and camphor in a ratio of 1:2 was the best formulation when compared with the marketed brands in view of both faster disintegration time and drug release as evident from the disintegration time of 11 sec and % drug release of 99.32% in 10 min. The stability studies were conducted and the formulation was found to be stable. These fast-dissolving tablets are useful in patients who may face difficulty in swallowing conventional tablets or capsules leading to ineffective therapy.

REFERENCES

1. M. Maheswari, K., Kumar Devineni, P., Deekonda, S., Shaik, S., Pravallika Uppala, N., & N. Nalluri, B. (2014). Development and Evaluation of Mouth Dissolving Films of Amlodipine Besylate for Enhanced Therapeutic Efficacy. ncbi.nlm.nih.gov
2. Narmada, G. Y., Mohini, K., Prakash Rao, B., Gowrinath, D. X. P., & Kumar, K. S. (2009). Formulation, evaluation and optimization of fast dissolving tablets containing Amlodipine Besylate by sublimation method. [PDF]
3. Rahane, R. D. & R. Rachh, P. (2018). A Review on Fast Dissolving Tablet. [PDF]
4. Rana, V., Pathak, B., Solanki, S., Patel, H., Maisuria, D., Modi, D. C., & Solanki, D. (2023). A Review on Fast Dissolving Sublingual Film for Systemic Drug Delivery. Pharma Science Monitor, 14(3). [HTML]
5. Maheshwari, S., Singh, A., Varshney, A. P., & Sharma, A. (2024). Advancing oral drug delivery: The science of fast dissolving tablets (FDTs). Intelligent Pharmacy. sciencedirect.com
6. Kawale, K. A., Autade, N. B., Narhare, H. S., & Mhetrea, R. L. (2023). A review on fast-dissolving oral film. Asian J Pharm Clin Res, 16(10), 7-17. semanticscholar.org
7. Dhanakishore, B., & Narapusetty, N. (2023). A review of immediate drug release dosage forms. Journal of Innovations in Applied Pharmaceutical Science (JIAPS), 11-19. saapjournals.org
8. Kshirsagar, T., Jaiswal, N., Chavan, G., Zambre, K., Ramkrushna, S., & Dinesh, D. (2021). Formulation & evaluation of fast dissolving oral film. World J. Pharm. Res, 10(9), 503-561. researchgate.net
9. Mehta, A. P., Kothari, M. S. S., Chaudhari, M. U. P., & Patil, M. K. S. (2022). Sublingual drug delivery system. International Journal Of All Research Writings, 4(12), 20-29. ijciras.com
10. Johannesson, J., Khan, J., Hubert, M., Teleki, A., & Bergström, C. A. (2021). 3D-printing of solid lipid tablets from emulsion gels. International journal of pharmaceutics, 597, 120304. sciencedirect.com
11. Galata, D. L., Könyves, Z., Nagy, B., Novák, M., Mészáros, L. A., Szabó, E., ... & Nagy, Z. K. (2021). Real-time release testing of dissolution based on surrogate models developed by machine learning algorithms using NIR spectra, compression force and particle size distribution as input data. International journal of pharmaceutics, 597, 120338. sciencedirect.com
12. Ghourichay, M. P., Kiaie, S. H., Nokhodchi, A., & Javadzadeh, Y. (2021). Formulation and quality control of orally disintegrating tablets (ODTs): recent advances and perspectives. BioMed Research International, 2021(1), 6618934. wiley.com
13. Ayyoubi, S., Cerda, J. R., & Fernández-García…, R. (2021). 3D printed spherical mini-tablets: Geometry versus composition effects in controlling dissolution from personalised solid dosage forms. International Journal of …. strath.ac.uk
14. Bhatt, P., Singh, S., Sharma, S. K., & Rabiu, S. (2021). Development and Characterization of Fast Dissolving Buccal Strip of Frovatriptan Succinate Monoydrate for Buccal Delivery. International Journal of Pharmaceutical Investigation, 11(1). [HTML]
15. Vinarov, Z., Abdallah, M., Agundez, J. A., Allegaert, K., Basit, A. W., Braeckmans, M., ... & Augustijns, P. (2021). Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review. European Journal of Pharmaceutical Sciences, 162, 105812. sciencedirect.com
16. Luo, Y., Hong, Y., Shen, L., Wu, F., & Lin, X. (2021). Multifunctional role of polyvinylpyrrolidone in pharmaceutical formulations. AAPS PharmSciTech. [HTML]
17. Liu, J., Grohganz, H., Löbmann, K., Rades, T., & Hempel, N. J. (2021). Co-amorphous drug formulations in numbers: Recent advances in co-amorphous drug formulations with focus on co-formability, molar ratio, preparation …. Pharmaceutics. mdpi.com
18. Jange, C. G., Wassgren, C. R., & Ambrose, K. (2023). The significance of tablet internal structure on disintegration and dissolution of immediate-release formulas: A review. Powders. mdpi.com
19. Momeni, M., Afkanpour, M., Rakhshani, S., Mehrabian, A., & Tabesh, H. (2024). A prediction model based on artificial intelligence techniques for disintegration time and hardness of fast disintegrating tablets in pre-formulation tests. BMC Medical Informatics and Decision Making, 24(1), 88. springer.com
20. Berardi, A., Bashara, L., Quodbach, J., Rahim, S. A., Perinelli, D. R., & Cespi, M. (2021). Advancing the understanding of the tablet disintegration phenomenon–An update on recent studies. International Journal of Pharmaceutics, 598, 120390. [HTML]
21. Bauhuber, S., Warnke, G., & Berardi, A. (2021). Disintegrant selection in hydrophobic tablet formulations. Journal of Pharmaceutical Sciences. jpharmsci.org
22. Musuc, A. M., Anuta, V., Atkinson, I., Sarbu, I., Popa, V. T., Munteanu, C., ... & Mitu, M. A. (2021). Formulation of chewable tablets containing carbamazepine-β-cyclodextrin inclusion complex and f-melt disintegration excipient. The mathematical modeling of the release kinetics of carbamazepine. Pharmaceutics, 13(6), 915. mdpi.com
23. Samineni, R., Chimakurthy, J., & Konidala, S. (2022). Emerging role of biopharmaceutical classification and biopharmaceutical drug disposition system in dosage form development: A systematic review. Turkish journal of pharmaceutical sciences, 19(6), 706. nih.gov
24. Gigante, V., Pauletti, G. M., Kopp, S., Xu, M., Gonzalez-Alvarez, I., Merino, V., ... & Bermejo, M. (2021). Global testing of a consensus solubility assessment to enhance robustness of the WHO biopharmaceutical classification system. ADMET and DMPK, 9(1), 23-39. srce.hr
25. Agnihotri, T. G., Paradia, P. K., & Jain, A. (2024). Biopharmaceutical Classification System: a strategic tool in pharmaceutical formulation. In Dosage Forms, Formulation Developments and Regulations (pp. 443-469). Academic Press. [HTML]
26. Truzzi, F., Tibaldi, C., Zhang, Y., Dinelli, G., & D′ Amen, E. (2021). An overview on dietary polyphenols and their biopharmaceutical classification system (BCS). International journal of molecular sciences, 22(11), 5514. mdpi.com
27. Bocci, G., Oprea, T. I., & Benet, L. Z. (2022). State of the art and uses for the biopharmaceutics drug disposition classification system (BDDCS): new additions, revisions, and citation references. The AAPS journal. springer.com
28. Floroiu, A., Loretz, B., Krämer, J., & Lehr, C. M. (2024). Drug solubility in biorelevant media in the context of an inhalation-based biopharmaceutics classification system (iBCS). European Journal of Pharmaceutics and Biopharmaceutics, 197, 114206. sciencedirect.com
29. Baryakova, T. H., Pogostin, B. H., Langer, R., & McHugh, K. J. (2023). Overcoming barriers to patient adherence: the case for developing innovative drug delivery systems. Nature Reviews Drug Discovery, 22(5), 387-409. nih.gov
30. Park, H., Otte, A., & Park, K. (2022). Evolution of drug delivery systems: From 1950 to 2020 and beyond. Journal of Controlled Release. nih.gov
31. Alqahtani, M. S., Kazi, M., Alsenaidy, M. A., & Ahmad, M. Z. (2021). Advances in oral drug delivery. Frontiers in pharmacology, 12, 618411. frontiersin.org
32. Gao, J., Karp, J. M., Langer, R., & Joshi, N. (2023). The future of drug delivery. Chemistry of Materials. acs.org
33. Jones, K. E., Hayden, S. L., Meyer, H. R., Sandoz, J. L., Arata, W. H., Dufrene, K., ... & Kaye, A. D. (2024). The evolving role of calcium channel blockers in hypertension management: pharmacological and clinical considerations. Current Issues in Molecular Biology, 46(7), 6315-6327. mdpi.com
34. Rahman, T., & Khan, M. F. (2024). Ca+ 2 Channel Blockers. In Medicinal Chemistry for Pharmacy Students (pp. 40-69). Bentham Science Publishers. sciendo.com
35. Singh, A., Verma, N. K., & Pandey, S. (2021). Preparation and Evaluation of Oral Dispersible Formulation of Amlodipine Beslate. International Journal of Pharmacy & Life Sciences, 12(3). [HTML]
36. Kokilambigai, K. S., Kavitha, J., Seetharaman, R., Lakshmi, K. S., & Sai Susmitha, A. (2021). Analytical and Bioanalytical Techniques for the Quantification of the Calcium Channel Blocker–Amlodipine: A Critical Review. Critical Reviews in Analytical Chemistry, 51(8), 754-786. researchgate.net
37. Alshaya, O. A., Alhamed, A., Althewaibi, S., Fetyani, L., Alshehri, S., Alnashmi, F., ... & Alshaya, A. I. (2022). Calcium channel blocker toxicity: a practical approach. Journal of Multidisciplinary Healthcare, 1851-1862. tandfonline.com
38. Shah, J. P., Akabari, A. H., Patel, S., & Surati, J. (). Amlodipine: A Review of Characteristics, Properties, Analytical Methods and Impact in the Green Chemistry. ijpsi.org. ijpsi.org
39. Saju, R. (2018). Formulation Development and Evaluation of Mouth Dissolving Tablets of Diltiazem Hydrochloride by Direct Compression Method. [PDF]
40. Pot?rniche, I. A., Saro?i, C., Terebe?, R. M., Szolga, L., & G?l?tu?, R. (2023). Classification of food additives using UV spectroscopy and one-dimensional convolutional neural network. Sensors, 23(17), 7517. mdpi.com
41. Chen, Z. (2024). Application of UV-vis spectroscopy in the detection and analysis of substances. In 3rd International Conference on Biotechnology, Life Science and Medical Engineering. semanticscholar.org
42. Czyczula Rudjord, Z., Reid, M. J., Schwermer, C. U., & Lin, Y. (2022). Laboratory development of an AI system for the real-time monitoring of water quality and detection of anomalies arising from chemical contamination. Water. mdpi.com
43. Yu, L., Li, Z., Huang, W., Ali, A., Chen, Y., Zhao, G., & Yao, S. (2024). Recovery and post-treatment processes for ionic liquids and deep eutectic solvents. Journal of Molecular Liquids, 124767. [HTML]
44. Chen, C., Wang, Z., Wu, J., Deng, Z., Zhang, T., Zhu, Z., ... & Gruev, V. (2023). Bioinspired, vertically stacked, and perovskite nanocrystal–enhanced CMOS imaging sensors for resolving UV spectral signatures. Science Advances, 9(44), eadk3860. science.org.