# A Stable Formulation of a Non-Steroidal Anti-inflammatory Drug, Ibuprofen and an Antihistamine drug, Famotidine for a Combination Therapy

Praneeth Rao Kakullamarri, Papireddy Tiyyagura, K Suresh Babu

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Praneeth Rao Kakullamarri, Papireddy Tiyyagura, K Suresh Babu. A Stable Formulation of a Non-Steroidal Anti-inflammatory Drug, Ibuprofen and an Antihistamine drug, Famotidine for a Combination Therapy. Journal of International Research in Medical and Pharmaceutical Sciences, 2023, A Stable Formulation of a NonSteroidal Anti-inflammatory Drug, Ibuprofen and an Antihistamine drug, Famotidine for a Combination Therapy, 18 (2), pp.38-50. 10.56557/JIRMEPS/2023/v18i28437. hal-04298887

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# A Stable Formulation of a Non-Steroidal Anti-inflammatory Drug, Ibuprofen and an Antihistamine drug, Famotidine for a Combination Therapy

Praneeth Rao Kakullamarri <sup>a</sup>, Papireddy Tiyyagura <sup>b</sup>
and K. Suresh Babu <sup>a*</sup>

## Authors' contributions

This work was carried out in collaboration among all authors. All authors read and approved the final
manuscript.

## Article Information

DOI: 10.56557/JIRMEPS/2023/v18i28437

Received: 12/09/2023

Accepted: 16/11/2023

Published: 21/11/2023

### Original Research Article

## ABSTRACT

**Purpose:** The present research study was focused on developing an oral dosage form with two highly incompatible drugs, a non-steroidal anti-inflammatory drug, Ibuprofen and an antihistamine drug, Famotidine to be administered as a combination therapy in a single dose and further assess the stability of the finished product.

**Methods:** A novel drug formulation was designed by employing mini tablets technology to manufacture Famotidine core tablets and the core tablets are further film coated with Opadry II coating solution to inhibit Famotidine contact with Ibuprofen matrix. Film coated Famotidine 30 mg mini-tablets were then encapsulated in Ibuprofen blend to improve the compatibility and stability of the drug product [1,2]. Each mini-tablet of Famotidine contain 5 mg dose of Famotidine and 6 such mini-tablets were encapsulated in each size "00" hard gelatin capsule containing Ibuprofen blend equivalent to 800 mg claim. The stability of the finished product was evaluated in accelerated stability conditions to ensure the impurities are well within the Pharmacopeia (USP) assigned limits.

<footnote><sup>a</sup> Faculty of Sciences, Lincoln University College, Malaysia.</footnote>

<footnote><sup>b</sup> Faculty of Pharmacy, Lincoln University College, Malaysia.</footnote>

<footnote>*Corresponding author: E-mail: babuiict@gmail.com;</footnote>
**Results:** The dissolution release of Ibuprofen and Famotidine is higher than 85 % in 15 minutes and is compared against the only available product in the combination therapy, DUEXIS® (Ibuprofen and Famotidine Tablets 800 mg and 26.6 mg). The stability of the final formulation is evaluated by placing the samples in 40°C/75 % RH storage condition for six months and the results of the pharmacopeia (USP) listed specified and unspecified impurities are well not more than 0.5 % w/w of the label claim. Famotidine and Ibuprofen are two highly in-compatible drugs for a combination therapy, and has been a challenge in the field to formulate for a combination therapy to improve patient compliance. The two drugs tend to form impurities at significant levels in direct physical contact during any stage of the manufacturing process.

**Keywords:** Ibuprofen; famotidine; stable formulation; combination therapy; mini-tablets.

# 1. INTRODUCTION

In this article, a non-steroidal anti-inflammatory drug (NSAID) selected is Ibuprofen, and an antihistamine drug of interest is Famotidine. Both Ibuprofen and Famotidine are in the market for nearly five decades. Ibuprofen in the market is widely used as the brand names Advil, Children's Ibuprofen, Advil Migraine, Motrin IB, NeoProfen, Caldolor, Wal-Profen, I-Prin, Ibuprofen IB, Provil [3] and Famotidine is well known by brands Pepcid AC, Pepcid indicated for antihistamine and antacid properties to treat ulcers, gastroesophageal reflux disease (GERD). Both drugs are available over the counter and considered as safe. The oral administration of NSAIDS such as Ibuprofen can cause ulcers such as gastritis, dyspepsia, and gastric and duodenal ulceration. Prolonged use of the NSAIDs especially, individuals with arthritis can lead gastric damage. Gastric and duodenal ulceration is a consequence of impaired mucosal integrity resulting from ibuprofen-mediated inhibition of prostaglandin synthesis and Famotidine blocks the action of the histamine type 2 (H2) receptor, leading to a reduction of acid secretion in the stomach [4,5]. Reducing stomach acid with famotidine during treatment with certain nonsteroidal anti-inflammatory drugs is reported to decrease incidence of gastrointestinal ulcers. Therefore, widely used practice to treat the condition is by co-administration of Ibuprofen and Famotidine as two separate dosages. The primary reason for this is the incompatibility between these two drugs [6]. Administering two drugs as separate dosage form for long term is been challenge to patients, especially geriatric patients and patient with minimum motor skills. Therefore, in this article a Novel stable formulation of Ibuprofen and Famotidine for a combination therapy in a single embodiment is developed for ease of administration and increase patient compliance. In this research, the final dosage form (Ibuprofen

and Famotidine mini tablets 800 mg and 30 mg) are stored in accelerated stability conditions 40 °C /75 % RH conditions for 6 months and evaluated for compatibility and stability.

A recently marketed product DUEXIS® (Ibuprofen and Famotidine) 800 mg and 26.6 mg Tablets developed by Horizon Therapeutics USA, Inc. is only available in the market as a co-therapy. DUEXIS® is developed as Tablet in tablet, where famotidine is compressed and film coated and then compressed in Ibuprofen blend [7,8,9]. In this article, the research was focused on novel formulation with mentioned two drugs in a single oral dosage form for co-therapy, ease of administration and patient compliance with emphasis on stability. A well known technology of mini-tablets is employed to compress Famotidine 30 mg tablets and encapsulated with Ibuprofen matrix in size "00" capsules for the co-administration of both the drugs [10,11,12].

# 2. MATERIALS AND METHODS

## 2.1 Materials

Microcrystalline cellulose, NF (Avicel PH112), (FMC BioPolymer, Pennsylvania, USA) Pre-gelatinized starch, NF (starch 1500) (Colorcon, USA), Magnesium Stearate, NF (Supplier and Distributor, Parchem, USA and Famotidine USP, (Dr. Reddy's, Hyderabad, India) Opadry II White (85F18422), (Colorcon, USA) Ibuprofen DC 85 W (BASF, USA) and Size "00" Hard gelatin Capsules (Capsugel, USA) were used.

**Method: Manufacturing of Famotidine Mini-Tablets 30 mg and Ibuprofen 800 mg Blend.**

A schematic representation of the concept to manufacture a combination drug in a same dosage form without impacting the stability of the dosage form over accelerated stability conditions is presented in Fig. 1 [13]. The Process flow for the current research study is presented in the Fig. 2.
<figure><img src="image_2.png" /><figcaption>**Fig. 1. Schematic Representation of Famotidine Mini-tablets Encapsulated in Size "00" Hard gelatin Capsule with a Ibuprofen Blend**</figcaption></figure>

<figure><img src="image_3.png" /><figcaption>**Fig. 2. Process Flow Representing the Manufacturing Process Ibuprofen and Famotidine Tablets 800 mg and 30 mg**</figcaption></figure>

**Preparation of Famotidine Mini Tablets:**

**Dry-Mixing of Famotidine Blend:** A blend of Microcrystalline cellulose, NF (Avicel PH112), Pre-gelatinized starch, NF (starch 1500), Magnesium Stearate, NF and Famotidine USP was manufactured. In the formulation, Microcrystalline cellulose, NF (Avicel PH112) at 66.67 % is used as a diluent, Pre-gelatinized starch, NF (starch 1500) at 13.33 % is used as a binder/disintegrant and Magnesium Stearate, NF at 3.33 % is used as lubricant. Refer Table 1 for the qualitative composition of the Famotidine blend. Microcrystalline cellulose, NF (Avicel PH112), Pre-gelatinized starch, NF (starch 1500) and Famotidine USP were passed through screen #30 and mixed in suitable double cone blender at 50 % occupancy for 30 min at 25 RPM and Lubricant was passed through 40 # mesh and mixed for 5 min at 25 RPM. Final mix blend was then sampled from ten locations from the double cone blender as mentioned in the Fig. 3 to evaluate blend uniformity. The sample of 3x the average weight is withdrawn from 10 different

locations from the double cone blender and analyzed for blend uniformity. Refer Table 7 for homogeneity results. Additionally, In-process blend of 50 grams is sampled to evaluate particle size distribution and perform physical characterization of blend. Moisture content was measured using Ohaus MB120 Moisture Analyzer at 105 °C for 10 min [14].

**Compression of Famotidine to Mini-Tablets:** Final mix blend of Famotidine is then compressed on 3 mm, round multi-tip tools (Refer 4 for representation of mini tools) on 21 station beta press, each punch has two 3 mm tips [15]. The average weight of each mini-tablet is 30 mg and tablets were compressed at three hardness (Low, target and High hardness) to get desired disintegration time and Friability. Throughout the compression process in-process samples were collected and evaluated for CQAs (critical quality attributes) such as Assay, Related compounds, Content uniformity (start, middle and end of the compression process), dissolution drug release and physical Parameters [16,17].
<figure><img src="image_4.png" /><figcaption>Fig. 3. Representation of Sampling Locations from the Double cone blender for Blend Uniformity sampling of Famotidine Blend</figcaption></figure>

<table><caption>Table 1. Quantitative composition of common blend for famotidine 30 mg tablets</caption><thead><tr><th>Ingredients</th><th>% w/w</th><th>mg/unit</th></tr></thead><tbody><tr><td>Famotidine Blend</td><td></td><td></td></tr><tr><td>Famotidine USP</td><td>16.67</td><td>5.00</td></tr><tr><td>Microcrystalline cellulose, NF (Avicel PH112)</td><td>66.67</td><td>20.00</td></tr><tr><td>Pre-gelatinized starch, NF (starch 1500)</td><td>13.33</td><td>4.00</td></tr><tr><td>Magnesium Stearate, NF</td><td>3.33</td><td>1.00</td></tr><tr><td>Total</td><td>100.00</td><td>30.00</td></tr><tr><td>Famotidine Mini-tablets Film Coating</td><td></td><td></td></tr><tr><td>Opadry II White</td><td>5.0 %</td><td>1.50</td></tr><tr><td>Tablet total weight</td><td></td><td>31.50</td></tr></tbody></table>

<table><caption>Table 2. Physical properties of famotidine blend</caption><thead><tr><th>Test</th><th>Results</th><th>Specification</th></tr></thead><tbody><tr><td>Description</td><td>White granular powder</td><td>White granular powder</td></tr><tr><td>% LOD</td><td>0.74</td><td>NMT 4.0 %</td></tr></tbody></table>

<table><caption>Table 3. Physical parameters evaluation of famotidine blend</caption><caption>Total Mass Withdrawn for Sieve Analysis- 50 grams</caption><thead><tr><th>Sieve #</th><th>Initial Weight of Sieve (g)</th><th>Final Weight of Sieve (g)</th><th>Amount Retained on Each sieve (g)</th><th>Fraction retained on each sieve</th><th>Cumulative fraction retained on each sieve</th></tr></thead><tbody><tr><td>40</td><td>275</td><td>275.0</td><td>0</td><td>0.00</td><td>0.00</td></tr><tr><td>60</td><td>252</td><td>252.5</td><td>0.5</td><td>0.01</td><td>1.00</td></tr><tr><td>80</td><td>247.5</td><td>252.5</td><td>5.0</td><td>0.10</td><td>11.00</td></tr><tr><td>100</td><td>270.5</td><td>276.0</td><td>5.5</td><td>0.11</td><td>22.00</td></tr><tr><td>200</td><td>266</td><td>285.5</td><td>19.5</td><td>0.39</td><td>61.00</td></tr><tr><td>Pan</td><td>366</td><td>385.5</td><td>19.5</td><td>0.39</td><td>100.00</td></tr><tr><td>Total</td><td>-</td><td>-</td><td>50.00</td><td></td><td></td></tr></tbody></table>

<table><caption>Table 4. Physical parameters evaluation of famotidine blend</caption><caption>Total Mass Withdrawn - 50.0 g</caption><thead><tr><th>Initial Mass (g)</th><th>Bulk Volume (mL)</th><th>Bulk Density (g/mL)</th><th>Final Volume (mL)</th><th>Tapped density (g/mL)</th><th>Compressibility Index</th><th>Hausner Ratio</th></tr></thead><tbody><tr><td>20.0</td><td>50.0</td><td>0.40</td><td>40</td><td>0.50</td><td>30</td><td>1.25</td></tr></tbody></table>
<table><caption>Table 5. Physical properties results of famotidine mini tablets</caption><thead><tr><th>Test</th><th>Results</th><th>Specification</th></tr></thead><tbody><tr><td>Description</td><td>3 mm, white, around tablets</td><td>3 mm, white, around tablets</td></tr><tr><td>Weight of Individual units</td><td>28.7 mg – 30.2 mg</td><td>6 % of individual target tablet weight (28.2 to 31.8 mg)</td></tr><tr><td>Group weigh of 10 tablets</td><td>301 mg</td><td>3 % of target 10 tablets 291 mg – 309 mg</td></tr><tr><td>Thickness (inch)</td><td>0.045 – 0.049</td><td>0.040 to 0.050</td></tr><tr><td>Hardness (kp)</td><td>1 – 2.5</td><td>NMT 4 kp</td></tr><tr><td>Friability (%)</td><td>0.2</td><td>NMT 1.0 %</td></tr><tr><td>Disintegration</td><td>30 sec.</td><td>NMT 3 min</td></tr></tbody></table>

<table><caption>Table 6. Film coating parameters of famotidine mini-tablets</caption><thead><tr><th>Parameters</th><th>Range</th><th>Observed parameters</th></tr></thead><tbody><tr><td>Coating weigh gain</td><td>3.0 – 7.0 % w/w</td><td>4.1 – 5.5 %</td></tr><tr><td>Inlet temperature (°c)</td><td>35 – 65</td><td>53 - 57</td></tr><tr><td>Exhaust temperature</td><td>30 – 50</td><td>38 - 43</td></tr><tr><td>Product Temperature</td><td>25 – 50</td><td>40 - 42</td></tr><tr><td>Pan speed</td><td>3 - 15</td><td>5 – 7</td></tr><tr><td>Atomization air</td><td>0.5 – 5</td><td>1.5</td></tr><tr><td>Spray rate</td><td>3 – 15</td><td>5 - 7</td></tr><tr><td>Drying time</td><td>30 min</td><td>20 min</td></tr><tr><td>% LOD</td><td>NMT 4 %</td><td>2.1 %</td></tr></tbody></table>

<table><caption>Table 7. Blend and content uniformity results for famotidine tablets 30 mg</caption><thead><tr><th>Samples</th><th>Blend Uniformity for(%Assay)</th><th>Content uniformity results from Start of the compression (%Assay)</th><th>Content uniformity results from Middle of the compression (%Assay)</th><th>Content uniformity results from End of the compression (%Assay)</th></tr></thead><tbody><tr><td>1</td><td>102.0</td><td>98.7</td><td>98.1</td><td>98.1</td></tr><tr><td>2</td><td>98.1</td><td>97.0</td><td>98.2</td><td>99.2</td></tr><tr><td>3</td><td>96.3</td><td>97.8</td><td>92.5</td><td>99.2</td></tr><tr><td>4</td><td>99.7</td><td>97.0</td><td>92.2</td><td>97.5</td></tr><tr><td>5</td><td>98.7</td><td>97.8</td><td>100.6</td><td>98.1</td></tr><tr><td>6</td><td>96.7</td><td>98.5</td><td>98.7</td><td>100.1</td></tr><tr><td>7</td><td>99.2</td><td>97.6</td><td>98.0</td><td>98.2</td></tr><tr><td>8</td><td>98.5</td><td>96.4</td><td>98.2</td><td>100.1</td></tr><tr><td>9</td><td>97.8</td><td>94.6</td><td>102.0</td><td>99.1</td></tr><tr><td>10</td><td>96.2</td><td>95.5</td><td>99.4</td><td>98.7</td></tr><tr><td>Mean</td><td>98.4</td><td>97.10</td><td>97.8</td><td>97.9</td></tr><tr><td>% RSD</td><td>1.8</td><td>1.3</td><td>3.5</td><td>1.2</td></tr></tbody></table>

<table><caption>Table 8. Physical parameters evaluation of ibuprofen blend</caption><caption>Total Mass Withdrawn for Sieve Analysis- 50 grams</caption><thead><tr><th>Sieve #</th><th>Initial Weight of Sieve (g)</th><th>Final Weight of Sieve (g)</th><th>Amount Retained on Each sieve (g)</th><th>Fraction retained on each sieve</th><th>Cumulative fraction retained on each sieve</th></tr></thead><tbody><tr><td>12</td><td>245</td><td>245</td><td>0.0</td><td>0.00</td><td>0.00</td></tr><tr><td>16</td><td>250</td><td>250.0</td><td>0.0</td><td>0.00</td><td>0.00</td></tr><tr><td>20</td><td>270</td><td>270</td><td>0.0</td><td>0.00</td><td>0.00</td></tr><tr><td>24</td><td>260</td><td>300.5</td><td>49.5</td><td>99.5</td><td>99.5</td></tr><tr><td>30</td><td>266</td><td>285.5</td><td>0.0</td><td>0.00</td><td>99.5</td></tr><tr><td>Pan</td><td>366</td><td>385.5</td><td>0.0</td><td>0.00</td><td>99.5</td></tr><tr><td>Total</td><td>-</td><td>-</td><td>49.50</td><td></td><td></td></tr></tbody></table>
**Film Coating of Famotidine Core Tablets:** The tablets compressed at target hardness are then film coated with Opadry II White (85F18422), material is procured from Colorcon USA. Core Famotidine Mini tablets were then coated 3 % on 9" Vector coating pan [18]. Opadry II white (85F18422) is added to purified water to prepare a solution at solid concentration of 12 % w/w. The coating solution is kept at gentle mixing throughout the coating process. Product temperature during coating process is kept at 39 °C - 43°C and spray rate throughout the process is 2-5 grams/per. Once the desired weight is achieved, film coated tablets are dried in the coating pan for 15 – 20 min on jog mode of the pan at 35 °C - 38°C exhaust temperature. % LOD of the tablets is evaluated to ensure the tablets dried appropriately. The process parameters of the film coating process are mentioned in Table 6.

**Manufacturing of Ibuprofen 800 mg Blend:** Ibuprofen Blend for Encapsulation: Ibuprofen

DC 85 W is procured from BASF for the experiments and same blend alone is encapsulated with Famotidine mini-tablets. Ibuprofen DC 85 is co-processed material of 85 % Ibuprofen and 15 % of Croscarmellose sodium, colloidal silicon dioxide and microcrystalline cellulose of USP grade. Therefore, for the claim of 800 mg of Ibuprofen in the formulation, 941.2 mg is encapsulated with Famotidine six mini tablets in capsule. Ibuprofen DC 85 W is passed through 16 # mesh (1190 microns) and 30 # mesh (595 microns) to separate coarse and fine particles, material retained on 16 # mesh is rejected and material passed through 30 # mesh is rejected, material retained on 16 # mesh is used for the batch to avoid weight variations during encapsulations. In-process tests such as composite assay, related compounds were performed, and physical characterization was performed on 50 grams' blend. Physical characterization results are presented in Tables 8 and 9.

<table><caption>Table 9. Physical parameters evaluation of ibuprofen blend</caption><thead><tr><th rowspan="2">Initial Mass (g)</th><th colspan="4">Total Mass Withdrawn - 50.0 g</th></tr><tr><th>Bulk Volume (mL)</th><th>Bulk Density (g/mL)</th><th>Final Volume (mL)</th><th>Tapped density (g/mL)</th></tr></thead><tbody><tr><td>20.0</td><td>50.0</td><td>0.55</td><td>32</td><td>0.64</td></tr></tbody></table>

<table><caption>Table 10. Dissolution Drug Release of Ibuprofen and Famotidine Mini Tablets (30 mg) and Marketed Product DUEXIS (Ibuprofen and Famotidine)</caption><thead><tr><th>Time in Min</th><th>DUEXIS (Ibuprofen)</th><th>Ibuprofen (800 mg) (Test)</th><th>DUEXIS (Famotidine 26.6 mg) (Reference)</th><th>Famotidine (30 mg) (Test product)</th></tr></thead><tbody><tr><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>10</td><td>99.2</td><td>99.5</td><td>79.8</td><td>80.5</td></tr><tr><td>20</td><td>99.5</td><td>100.7</td><td>89.3</td><td>90.5</td></tr><tr><td>30</td><td>99.8</td><td>100.9</td><td>100.2</td><td>98.5</td></tr><tr><td>45</td><td>101.2</td><td>101.0</td><td>100.6</td><td>100.1</td></tr><tr><td>60</td><td>101.2</td><td>101.1</td><td>100.6</td><td>100.2</td></tr></tbody></table>

<table><caption>Table 11. Gradient dissolution design</caption><thead><tr><th>Time (Minutes)</th><th>%Mobile Phase-A</th><th>%Mobile Phase-B</th></tr></thead><tbody><tr><td>0.0</td><td>100</td><td>0</td></tr><tr><td>3.0</td><td>100</td><td>0</td></tr><tr><td>8.4</td><td>65</td><td>35</td></tr><tr><td>20.0</td><td>55</td><td>45</td></tr><tr><td>30.0</td><td>10</td><td>90</td></tr><tr><td>32.0</td><td>10</td><td>90</td></tr><tr><td>33.5</td><td>100</td><td>0</td></tr><tr><td>40.0</td><td>100</td><td>0</td></tr></tbody></table>
<table><caption>**Table 12. List of famotidine related specified and unspecified impurities analyzed in ibuprofen and famotidine (mini tablets)**</caption><thead><tr><td>Name</td><td>Chemical Name</td></tr></thead><tbody><tr><td>Famotidine sulfoxide</td><td>3-[[2-(Diaminomethyleneamino) thiazol-4-yl]methylsul_nyl]-N'-sulfamoyl- propanimidamide</td></tr><tr><td>Famotidine propionic acid (famotidine related compound F)</td><td>3-[[2-(Diaminomethyleneamino) thiazol-4-yl]methylthio]propanoic acid</td></tr><tr><td>*Famotidine amidine (famotidine related compound A)</td><td>3-[[2-(Diaminomethyleneamino)thiazol-4-yl]methylthio]propanimidamide</td></tr><tr><td>Famotidine sulfamoyl propanamide (famotidine related compound C)</td><td>3-[[2-(Diaminomethyleneamino) thiazol-4-yl]methylthio]-N'-sulfamoylpropanamide</td></tr><tr><td>Famotidine</td><td>3-[[2-(Diaminomethyleneamino)thiazol-4-yl]methylthio]-N'-sulfamoyl-propanimidamide</td></tr><tr><td>Famotidine propanamide (famotidine related compound D)</td><td>N-Cyano-3-[[2-(diaminomethyleneamino) thiazol-4-yl]methylthio]propanimidamide</td></tr><tr><td>Famotidine cyanoamidine (famotidine related compound G)</td><td>N-Cyano-3-[[2-[(diaminomethyleneamino)thiazol-4-yl]methylthio]propanimidamide</td></tr><tr><td>*Famotidine dimer (famotidine related compound B)</td><td>3,5-B i s[2-[[2-[ (diaminomethylene) amino]thiazol-4-yl]methylthio)ethyl]4H-1,2,4,6-thiatriazine 1, 1 -dioxide</td></tr><tr><td>Famotidine disulfide (famotidine related compound E)</td><td>2,2'-[ 4,4'-Disulfanediylbis(methylene) bis(thiazole-4,2-diyl)]diguanidine</td></tr></tbody></table>

<table><caption>**Table 13. List of ibuprofen related specified and unspecified impurities analyzed in ibuprofen and famotidine (mini tablets)**</caption><thead><tr><td>Name</td><td>Chemical Name</td></tr></thead><tbody><tr><td>Ibuprofen Related Compound J</td><td>2-(4-isobutyryl phenyl)-propionic acid</td></tr><tr><td>Ibuprofen Related Compound L</td><td>2-(4'-(1-Hydroxy-2-Methylpropyl) Phenyl Propionic Acid (2RS)-2-(4-Ethylphenyl)propanoic acid</td></tr><tr><td>Ibuprofen Related Compound N</td><td>(2RS)-2-[3-(2-Methylpropyl)phenyl] propanoic acid + 2-[4-(1-Methylpropyl)phenyl]propanoic acid</td></tr><tr><td>*Ibuprofen Related Compound A + Ibuprofen Related Compound O</td><td>(RS)-2-(4-(2-methylpropylphenyl) propanoic acid</td></tr><tr><td>Ibuprofen</td><td>4'-Isobutylacetophenone</td></tr><tr><td>Ibuprofen Related Compound C</td><td></td></tr></tbody></table>

<table><caption>**Table 14. Stability results of ibuprofen and famotidine tablets**</caption><thead><tr><td>Impurities</td><td>Day- 1 (Initial)</td><td>40 /75 % RH 6 months</td></tr></thead><tbody><tr><td>% Sulfamides</td><td>0.32</td><td>0.35</td></tr><tr><td>% Ibuprofen Impurities</td><td>0.06</td><td>0.05</td></tr><tr><td>% Assay of Famotidine</td><td>100.1</td><td>100.4</td></tr><tr><td>% Assay of Ibuprofen</td><td>100.5</td><td>100.2</td></tr><tr><td>% Total Impurities</td><td>0.40</td><td>0.41</td></tr><tr><td>% Drug Content of Ibuprofen</td><td>100.5</td><td>100.2</td></tr><tr><td>% Drug Content of Famotidine</td><td>100.1</td><td>100.0</td></tr></tbody></table>

**Encapsulation of Famotidine Mini-Tablets in Ibuprofen Blend:** Film coated Famotidine mini-tablets are then encapsulated in Ibuprofen blend. A dual hopper, one holding Ibuprofen blend and other holding Famotidine Mini-tablets were set up on ACG AF 40 T Capsule filler. Famotidine six mini-tablets are filled in size "00" hard gelatin capsules manufactured by ACG (India). The Ibuprofen blend filler was dialed to 941 mg; the

target whole capsule weights are 1127 mg with limits of + 7.5 % w/w (1042.5 mg – 1211.5 mg). The Net weight variations from the encapsulation process are compiled on Minitab18® I chart. (Refer Fig. 7). Once the encapsulation is completed the samples are stored in HDPE (High density polyethylene) 90 CC bottles for 6 months at 40 °C /75 % RH stability condition.
<figure><img src="image_5.png" /><figcaption>Fig. 4. Representation of multi-tip tools for compression of mini-tablets</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>Fig. 5. Blend uniformity results of famotidine blend</figcaption></figure>

<figure><img src="image_7.png" /></figure>

Descriptive Statistics: Start, Middle, End

Statistics

<table><caption>Fig. 6. Results for famotidine mini-tablets content uniformity</caption><thead><tr><th>Variable</th><th>N</th><th>N*</th><th>Mean</th><th>SE Mean</th><th>StDev</th><th>Minimum</th><th>Q1</th><th>Median</th><th>Q3</th><th>Maximum</th></tr></thead><tbody><tr><td>Start</td><td>10</td><td>0</td><td>97.090</td><td>0.409</td><td>1.294</td><td>94.600</td><td>96.175</td><td>97.300</td><td>97.975</td><td>98.700</td></tr><tr><td>Middle</td><td>10</td><td>0</td><td>97.790</td><td>0.993</td><td>3.140</td><td>92.200</td><td>96.625</td><td>98.200</td><td>99.700</td><td>102.000</td></tr><tr><td>End</td><td>10</td><td>0</td><td>98.830</td><td>0.275</td><td>0.871</td><td>97.500</td><td>98.100</td><td>98.900</td><td>99.425</td><td>100.100</td></tr></tbody></table>
<figure><img src="image_8.png" /></figure>

Statistics

<table><caption>Fig. 7. Encapsulation net weights of ibuprofen and famotidine tablets 800 mg and 30 mg</caption><thead><tr><th>Variable</th><th>N</th><th>N*</th><th>Mean</th><th>SE Mean</th><th>StDev</th><th>Minimum</th><th>Q1</th><th>Median</th><th>Q3</th><th>Maximum</th></tr></thead><tbody><tr><td>Net weights</td><td>50</td><td>0</td><td>1086.7</td><td>1.12</td><td>7.93</td><td>1070.0</td><td>1081.0</td><td>1087.0</td><td>1090.3</td><td>1105.0</td></tr></tbody></table>

<figure><img src="image_9.png" /><figcaption>Fig. 8. Dissolution drug release of ibuprofen and famotidine mini tablets (30 mg) and marketed product duexis (ibuprofen and famotidine) analyte measured is famotidine</figcaption></figure>

<figure><img src="image_10.png" /><figcaption>Fig. 9. Dissolution drug release of ibuprofen and famotidine mini tablets (30 mg) and marketed product duexis (ibuprofen and famotidine) analyte measured is ibuprofen</figcaption></figure>
## Physio-chemical Characterization

**Bulk density:** Blend physical characterization was performed on the Famotidine final mix; bulk density of the blend is measured as the ratio of mass of blend (50 grams) in 50 ml volume measuring cylinder. Bulk density of the Famotidine blend is calculated per the formula below, where M is weight of blend used in grams and V₀ is the volume of the blend occupied in measuring cylinder [19].

$$ \text{Bulk density (g/ml)} = \frac{M}{V_0} $$

**Tapped Density:** Famotidine final mix blend is also evaluated for tapped density, 50 grams of blend is weighed and transferred to a measuring cylinder and 10, 500 and 1250 taps were performed to see the difference in volume and the difference after 1250 volumes is more than 5 ml, therefore, 300- taps was performed on the same powder and difference is below 1 ml. Tapped density of the powder was calculated using the below formula, where M is weight of blend used in grams and Vᵢ is the volume of the blend occupied in measuring cylinder after final tapping, additionally, compressibility Index and Husner ratio are calculated for the blend.

$$ \text{Tapped density (g/ml)} = \frac{M}{V_f} $$

**Particle size analysis:** Particle size distribution of the blend was done using Retsch Vibratory Sieve Shaker AS 200 Digit CA using 8 "screens", the amplitude was kept 1.0 mm throughout the test. Particle size Results are presented in Table 3.

**In-vitro dissolution drug Release Method:** The dissolution drug release from the finished product, six capsules of Ibuprofen and Famotidine Capsules 800 mg and 30 mg were evaluated in following conditions, the method is employed from FDA [20], Dissolution data base of Ibuprofen and Famotidine Tablets 800 mg and 26.6 mg Tablets. Per the method, 900 ml of 0.05 M Phosphate Buffer, pH 7.2 equipped with paddle rotating at 50 RPM, the dissolution media is maintained at 37° C ± 0.5 ° C temperature. At predetermined time points 5, 10, 15, 20, 30 and 45 min 10 ml of samples were collected from the dissolution bowls and same amount of fresh dissolution media is replenished throughout the study. The samples collected were filtered through 0.45 µm filter membrane (Millipore, USA) and assessed for Ibuprofen and Famotidine by

HPLC. The dissolution drug results of Ibuprofen and Famotidine analytes from the current research are compared against the marked product DUEXIS (Ibuprofen and Famotidine Tablets). Results are presented in Table 10 and Figs 8 and 9.

**Evaluation Ibuprofen and Famotidine Drug Content in Finished Product Capsules:** The amount/potency of drug, Ibuprofen and Famotidine present in the finished dosage form is evaluated by using sample preparation method described below for related compounds estimation, samples were prepared in duplicates to study the variation.

**Stability of Ibuprofen and Famotidine (Mini Tablets):** The stability of the drug product is extensively evaluated for all the Ibuprofen and Famotidine related impurities listed in United states pharmacopeia (Refer 12 and 13) which tend to form with interaction of Ibuprofen and Famotidine, the stability was evaluated by upon exposing the samples for 6 months at 40 °C /75 % RH conditions [21].

**UPLC Analysis:** Ibuprofen and Famotidine related impurities were analyzed on UPLC (Ultra Performance Liquid Chromatography) (Waters, Acquity) using an autosampler, Waters Sample Manager- FTN) a Acquity UPLC HSS T3, 30 X 100 mm column was used on the system for the analysis. The wave length of 265 nm is identified as optimal for assessing of both the analytes, Ibuprofen and Famotidine. Column oven temperature and samples temperature are maintained at 35°C and 10 °C respectively. The injection volume is 5 µL throughout the run. A gradient method designed in Table 11 was used to evaluate the specified and unspecified impurities in the finish product.

**Materials and Methods for UPLC Analysis:** Reagents: 1) Sodium Acetate Trihydrate (AR grade) 2) Sodium Acetate anhydrous (AR grade) 3) Glacial Acetic acid (AR grade) 4) Methanol (HPLC grade) 5) Acetonitrile (HPLC grade) 6) Triethylamine (AR grade) 7) Famotidine reference standard 8) Ibuprofen reference standard.

## Mobile Phase Preparation:

**Buffer solution:** was prepared with sodium acetate and pH of the solution is adjusted to 6.0 with glacial acetic acid and filtered through 0.45-µm membrane filter.
**Mobile phase A preparation:** Mobile phase A was prepared by mixing above prepared buffer solution and Acetonitrile in the ratio of (93:7 v/v) respectively.

**Mobile phase B preparation:** Mobile phase B was prepared by mixing above prepared buffer solution, Methanol and Acetonitrile in the ratio of ratio of 10/45/45, v/v/v respectively.

**Preparation of Diluent for sample:** Buffer preparation sample: Accurately weighed and transfer 4 g of Sodium Acetate anhydrous into 1000 mL of DI Water and added 2.0 mL of Triethylamine. pH of the solution was adjusted to 5.5 using glacial acetic acid.

**Diluent-1 preparation:** Mixed above prepared Buffer and Methanol in the ratio (1:1 v/v) respectively.

**Sample Preparation Method:** 1. The finished product average weight was determined by weighing 100 capsules. 2. Accurately weighed and transferred five (5) capsules to a 1000 mL volumetric flask. 3. Added about 100 mL of buffer. 4. Mixed for about 15 minutes. 5. Added about 70% volume of the flask with diluent-1 and mixed for 30 minutes. 6. Added about 100 mL of methanol. 7. Diluted to volume with diluent-1 and mix well using the shaker. 8. Centrifuged a portion of solution on centrifuge for 15 minutes. Used clear solution for injection in UPLC.

**Calculations for Famotidine Related Impurities:**

(%) of Specified or Unspecified degradation products of Famotidine:

% Impurity =

$$ \frac{A_u}{As} \times C \times P \times \frac{1000 \text{ mL}}{\text{SpIWt}} \times \frac{\text{ATW}}{30 \text{ mg}} \times \frac{1}{\text{RRF}} \times 100 $$

Where,

Au is the peak area of impurity in sample preparation

As is average peak area of Famotidine in Low level standard preparation

C is the concentration of Famotidine in Low level standard preparation in mg/mL

P is Purity Factor Famotidine in decimal form

SpIWt is the weight of sample taken in mg

ATW is the Average Tablet weight in mg

100 is the conversion factor for percent

RRF is the Relative Response Factor for known related compounds (Table 1)

RRF for Unknown impurities consider as 1.0

**Calculations for Ibuprofen Related Impurities:**

(%) of Specified or Unspecified degradation products of Ibuprofen:

% Impurity =

$$ \frac{A_u}{As} \times C \times P \times \frac{1000 \text{ mL}}{\text{SpIWt}} \times \frac{\text{ATW}}{800 \text{ mg}} \times \frac{1}{\text{RRF}} \times 100 $$

Where,

Au is the peak area of impurity in sample preparation

As is average peak area of Ibuprofen in Low level standard preparation

C is the concentration of Ibuprofen in Low level standard preparation in mg/mL

P is Purity Factor Ibuprofen in decimal form

SpIWt is the weight of sample taken in mg

ATW is the Average Tablet weight in mg

100 is the conversion factor for percent

RRF is the Relative Response Factor for known related compounds

RRF for Unknown impurities consider as 1.0

**3. RESULTS AND DISCUSSION**

During the manufacturing process, the Quality control attributes (CQAs) of the drug product are identified and monitored to access the feasibility of the manufacturing process and specifications for each test are assigned per the industrial and united states pharmacopeia specifications.

During the manufacturing of Famotidine 30 mg mini-tablets, blend description, % LOD, blend uniformity we're analyzed, refer results in Tables 2, 3 and 4. Particle size distribution data revealed that the 60 % fraction the blend is retained on 200 screen. Compressibility index and Hausner ratio are the indirect measure and indications of the compressibility of the blend, per the results it was evident that blend is passable to fair to compress. However, during the actual compression process compression of the famotidine core tablets was successful without any weigh variations. From the physical characterization results, it was evident that the adopted manufacturing process and defined process parameters are appropriate to achieve results well within the assigned specifications.
Final Mix blend is compressed using 3 mm, plain, round mini compression tools on FlexiTab XL. The average and group weights of tablets are well with the limits of 5 % and 7.5% respectively, disintegration of tablets is NMT 60 seconds and Friability of tablets is NMT 1.0 %, results are presented in Table 5. During the compression tablets were collected during start, middle and end of the compression process to evaluate for homogeneity of core tablets. From the results, it was evident that the Tablets were homogeneous, Refer Table 7 for the results, the % RSDs are from 1.2 % - 3.5 % in the samples collected throughout the compression process and for the blend uniformity results also revealed that the blend is homogenous. The tablets were then coated with Opadry II white (PVA based) to inhibit interaction with Ibuprofen blend. The Ibuprofen matrix, prescreened Ibuprofen DC 85 W, procured from BASF was encapsulated. Since the amount of Ibuprofen is more than 85%, blend was warranted to be homogenous and only composite assay was considered evaluated, to compensate, amount of Ibuprofen DC 85 W per capsule is 941.2 mg. Ibuprofen DC 85 W 800 mg equivalent and Famotidine 30 mg mini tablets were then encapsulated and tested for drug product CQAs like, Related compounds, Assay and dissolution drug release in 900 ml, 0.05 M Phosphate Buffer, pH 7.2, USP paddle, collected samples at 5, 10, 15, 20, 30 and 45 min. From the results it was evident that the, drug release of both the analytes, Ibuprofen and Famotidine are more than 85 % for two minutes and are identical to marketed product DUEXIS® (Ibuprofen and Famotidine Tablets) 800 mg and 26.6 mg tablets. Results are presented in Table 10 and Figs. 8 and 9. From the results it can be concluded that the designed formulation in this article Ibuprofen and Famotidine Mini-tablets will be potential prospect to address the incompatibility and stability issues with the incompatible drugs. This is warranted by the stability results of the samples stored in accelerated conditions for six months.

## 4. CONCLUSION

The Designed formulation technology of Film-coated mini-tablets of first drug, (Famotidine) encapsulated in the blend of second drug, (Ibuprofen) is ideal for drugs which are incompatible for a combination therapy in a single dosage form. In the current research to was evident that, the, Ibuprofen 800 mg and Famotidine Mini tablets 30 mg is highly

compatible and stable at room temperature and accelerated stability conditions.

## CONSENT AND ETHICAL APPROVAL

It is not applicable.

## COMPETING INTERESTS

Authors have declared that no competing interests exist.

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