Development of Co-Amorphous Loratadine–Citric Acid Orodispersible Drug Formulations

Abstract

This study aimed at the preparation and characterization of co-amorphous loratadine–citric acid orally disintegrating dosage forms (ODx). A co-amorphous loratadine–citric acid was prepared by solvent evaporation method in three different molecular ratios. DSC, FTIR, and dissolution studies have been conducted for the binary system. The co-amorphous system was used to obtain oral lyophilizates and orally disintegrating tablets by direct compression. Diameter, thickness, hardness, disintegration time, uniformity of mass, and dissolution was determined for the dosage forms. DSC curves showed a lack of sharp endothermic peaks for the binary systems. FTIR spectra presented a hypsochromic modification of the characteristic peaks. Dissolution studies indicated a five-fold increase in the dissolved amount compared to pure loratadine in water. Disintegration times of direct compression ODx varied in the range of 34–41 s and for freeze-dried ODx in the range of 8–9 s. Friability was under 1% in all cases. The dissolution of loratadine in buffer solution at pH = 1 was almost complete. In conclusion binary systems of loratadine and citric acid enhance solubility and combined with the orally disintegrating pharmaceutical form also increase patient compliance.

1. Introduction

Loratadine, a second-generation antihistaminic drug, also exhibiting anti-inflammatory properties, is widely used in the treatment of allergy symptoms [1,2]. Loratadine shows a good permeability but extremely poor water solubility, belonging to class II of the Biopharmaceutics Classification System (BCS) [3]. Due to the pH-dependent solubility (pKa 4.3) in patients with insufficient gastric acid, bioavailability is even lower. Designing a pharmaceutical form implies improving the solubility and the dissolution rate of loratadine.

Co-amorphous systems are homogenous blends of active pharmaceutical ingredients (API) in amorphous form with a low molecular weight partner molecule, called co-former, stabilizing the API [4]. A co-amorphous formulation is a form of solid dispersion, in which the drug and the co-former are required to be miscible or soluble in each other to form a homogenous single-phase system [5]. Co-formers stabilize the API through intermolecular interactions, such as hydrogen bonds and salt formation [6]. Various molecules may be used as co-formers: amino acids, citric acid, tannic acid, saccharin, nicotinamide, and aspartame [7,8,9,10,11,12]. These small molecules overcome the disadvantages of a high amount of polymer in solid dispersions [5]. Co-amorphous systems are highly effective in increasing solubility and bioavailability.

Orodispersible drug formulations (ODx) disintegrate rapidly, within seconds, placed on the tongue without water [13]. ODx are popular in patients because of their ease of administration in pediatrics, elder patients, and patients with swallowing difficulties. The formulation of ODx is challenging for various reasons. In the case of bitter drugs taste masking is imperative for good palatability [14]. In-process handling and packing ask for proper friability and mechanical resistance. Humidity sensitivity needs thoughtfully selected packaging, as ODx need to be shielded from humidity by a specific product container [15]. Preparation methods include patented ones such as Wowtab^®, Orasolv^®, Flashtab^® and Durasolv^®, Zydis^®, Flashdose^®, and Oraquick^® technologies [16]. Commonly used obtaining methods are freeze-drying, melt extrusion, direct compression, spray-drying, molding, and the cotton candy process. On large-scale fabrication, the most used is direct compression, usually with superdisintegrants in the composition [13]. Freeze-dried ODx are very light, with a highly porous structure, in this case, the disintegration usually occurs very fast [17,18].

The co-amorphous loratadine–citric acid system obtained by Wang et al. [19] in 2017 proved enhanced physical stability. Loratadine, a widely used long-lasting non-sedating antihistaminic drug, with low solubility, is intensively studied for solubility enhancement. Higher solubility may be reached by combining the API with PEG 6000 [20], PVP K30 [21], Gelucire^® 50/13 [22], HPMC K100, Kollidon^® CL and mannitol [23], Poloxamer [24], Crospovidone and Kollicoat^® [25], or PVP K30 at different ratios [26]. PEG 6000 and PVP K30 solid dispersion of loratadine were embedded in ODx by direct compression using superdisintegrants, proving the efficacy of PEG in solubility enhancement [27].

Loratadine ODT by direct compression with starch-based superdisintegrants showed a disintegration time below 25 s [28]. Co-processed mannitol and crospovidone had superior results lowering the disintegration time [29]. Pharmaburst^® technology [30] ensured 36–48 s disintegration and by adding Croscarmellose, a 27 s disintegration time may be achieved. Croscarmellose decreased disintegration and ensured almost 100 % API dissolution after 10 min [31]. Camphor as a subliming agent, combined with sodium starch glycolate 6% disintegrates faster than 15 s [32]. The higher stability of ODx with eco-friendly excipients, Pharmaburst^® 500 and Flowlac^® 100 by direct compression was achieved [33]. Loratadine–containing polymer-based oral strips with HPMC E15 LV Premium [34], HPMC sorts E3, E6, and E15 provide immediate release. [35]. Loratadine nanocrystals can be obtained by freeze-drying with Pluronics^® 127 and PVK K17 to improve oral bioavailability [3]. The lyophilized powder of the loratadine nanosuspension showed superior dissolution compared to commercial tablets [36]. Milk oral lyophilizates with bovine milk and infant formulae fulfilled the requirement for oral lyophilizates [37].

This study aims to obtain a co-amorphous loratadine–citric acid system to improve solubility and bioavailability and embed it into ODx prepared by direct compression and lyophilization for enhanced patient compliance.

2. Materials and Methods

2.1. Materials

Loratadine was kindly supplied by Arena Group SA (Voluntari, Romania); citric acid was purchased from Sigma-Aldrich Chem. Co. (Saint Louis, MO, USA); Kollidon VA64 and Kollidon CL were from BASF Pharma (Ludwigshafen, Germany). Sorbitol and lactose were from Merck (Rahway, NJ, USA); mannitol VWR Chemicals (Radnor, PA, USA); gelatin was from Al-Nasr Pharmaceutical Chemicals Co. (Obour, Egypt); Sodium-croscarmellose-Vivasol GF and Microcrystalline cellulose-Vivapur were from JRS Pharma GmbH & Co. KG (Rosenberg, Germany); Magnesium-stearate; Silicon Dioxide—Aerosil^® 200 were from Evonik-Degussa GmbH (Essen, Germany). All other reagents were of analytical grade.

2.2. Methods

2.2.1. Preparation of Co-Amorphous Loratadine–Citric Acid System

Binary mixtures of loratadine and citric acid had been prepared in three different molar ratios 1:1, 2:1, and 3:1 by the solvent evaporation technique. Accurately weighted amounts of loratadine and citric acid had been dissolved in 20 mL of absolute ethanol. The solvent was evaporated for 24 h under ambient conditions, then introduced in a hot air oven at 50 °C until complete drying. The final product was powdered and sieved throughout a 315 µm sieve and stored at room temperature in a desiccator.

2.2.2. Characterization of Co-Amorphous Loratadine–Citric Acid System

Differential Scanning Calorimetry (DSC)

DSC was performed by a Shimadzu DSC 60 apparatus, in the temperature range of 30–300 °C, with a heating rate of 5 °C/min in a dynamic air atmosphere; 5 mg of accurately weighted samples (loratadine, citric acid, and the three binary mixtures) were sealed in 40 µL aluminum pans, using aluminum oxide as a reference. Data analysis was performed using DSC60 software (version 6.21).

Fourier Transform Infrared Spectroscopy (FTIR)

The FTIR spectra were collected using a Thermo Nicolet 380 spectrometer (Thermo Electron Corporation, Madison, WI, USA) with a resolution of 4 cm⁻¹, over the range 4000–1000 cm⁻¹ with 32 scans. The samples (loratadine, citric acid, and the three binary mixtures) were placed on a Zn-Se crystal surface. Data analysis was performed using Omnic Spectra software (version 8.2).

2.2.3. Dissolution Test

The dissolution test was performed with Biobase BK-RC3 apparatus with a rotating basket, in 200 mL of distilled water, at a rotation speed of 50 rpm and a temperature of 37 ± 0.5 °C. Accurately weighted amounts corresponding to 10 mg of loratadine were used. After 5, 10, 15, 20, 30, and 60 min, 5 mL aliquots were removed and replaced with fresh distilled water. After filtration through a 0.45 µm filter, loratadine content was determined using UV spectroscopy with the apparatus UV-1800 240V IVDD, Shimadzu (UV-VIS) at a wavelength of 248 nm. All dissolution samples were performed in triplicates.

2.2.4. Preparation of Orodispersible Drug Formulations

Two methods have been used: direct compression (DC,

Table 1. ODx composition prepared by direct compression.

Components (mg)	DC1:1 *	DC2:1 *	DC3:1 *
Loratadine–citric acid	15.01 **	12.50 **	11.67 **
Kollidon® VA64	6	6	6
Kollidon® CL	10	10	10
Sorbitol	5	5	5
Lactose	160	162.5	163.34
Aerosil	2	2	2
Magnesium-stearate	2	2	2

* Molar ratios, ** Equivalent of 10 mg loratadine.

) and lyophilization (OL,

Table 2. ODx composition prepared by lyophilization.

Components (mg)	OL1:1 *	OL2:1 *	OL3:1 *
Loratadine–citric acid	15.01 **	12.50 **	11.67 **
Gelatin	6	6	6
Sodium-croscarmellose	5	5	5
Microcrystalline cellulose	5	5	5
Sorbitol	64.37	65.62	66.04
Mannitol	52.31	52.94	53.145
Lactose	52.31	52.94	53.145

* Molar ratios, ** Equivalent of 10 mg loratadine.

).

Kollidon^® VA64, a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 6:4 by mass was used in 3% concentration for direct compression. Kollidon^® CL—insoluble crosslinked polyvinylpyrrolidone, a superdisintegrants and dissolution enhancer, was mixed in 5% concentration of the total amount. Lactose was used as a filler, sorbitol sugar alcohol as a sweetener, magnesium stearate as an anti-adherent and lubricant, and Aerosil as a glidant. The ingredients were accurately weighed. The powders were mixed concerning the rule of blending powders (increasing quantities, descending densities). The tablets were obtained using an eccentric tableting machine, Korsch 0 (Berlin, Germany), with punches of 9 mm. The prepared tablets were kept in tightly closed containers, protected from light, and humidity in a desiccator at room temperature (15–25 °C).

OL was prepared using gelatin as a matrix former. Gelatin was first dissolved in distilled water at about 50 °C. Mannitol, conferring crystallinity and hardness to OL, was used as a filler. Accurately weighed amounts of cellulose, sodium-croscarmellose a superdisintegrant, sorbitol, lactose, mannitol, and loratadine–citric acid were then added to the gelatin solution. The suspension was immediately poured into each pocket of a blister pack, each pocket with a diameter of 13 mm and a depth of 4 mm, resulting in a dose of 10 mg loratadine per tablet. The tablet blister packs were immediately transferred to a Biobase BK FD10S lyophilizer (Biobase, Jinan, China) with a condenser temperature of −55 °C and pressure under 10 Pa for 24 h.

2.2.5. Evaluation of ODx

The Physical Appearance of ODx

The ODx must present a uniform aspect, and intact margins and the smell, taste, and color should be following the properties of the excipients and API used.

Thickness and Diameter

Thickness and diameter (mm) were determined using a digital micrometer (Yato Digital Micrometer, Mumbai, India, resolution 0.001 mm) and expressed as the average of the values determined for 20 tablets.

Hardness

The crushing strength was obtained using the TFUT3 Tablet Four usage Tester Model (Biobase, Jinan, China). For this, 10 ODx from each formulation were tested and the result was expressed in Newtons (N).

Friability

Friability was evaluated according to requirements stipulated by the 10th European Pharmacopoeia (Ph. Eur. 10), using 20 tablets for each formulation. To establish this parameter, the TFUT3 Tablet Four Usage Tester Model (Biobase, Jinan, China) was used. The apparatus drums had a rotation speed of 25 rot/min for four minutes. The weight loss was expressed in percentages, with the upper limit admitted being 1%.

Uniformity of Mass

Uniformity of mass was calculated using a four-decimal balance (KERN, Balingen, Germany). For each formulation, 20 tablets were weighed, and the uniformity of mass was calculated.

According to the 10th European Pharmacopoeia, for 18 of the tablets, the standard deviation of ±5% is accepted while for 2 a ±10% deviation from the declared mass is accepted.

Disintegration

The disintegration time was determined using the TFUT3 Tablet Four Usage TesterModel (Biobase, Jinan, China) at 37 ± 1 °C, the disintegration method used disks in 900 mL water on six tablets from each formulation.

Dissolution Test

Dissolution was performed as previously described in point 2.2.3 using simulated stomach fluid as dissolution media.

Statistical Analysis

All results were expressed as mean ± standard deviation (SD). The results were statistically analyzed with a Student’s t-test Microsoft Excel version 2108. The significance level (p) was set as 0.05.

3. Results

3.1. Preparation of Co-Amorphous Loratadine–Citric Acid System

As the first step binary mixtures were prepared to contain 1:1, 2:1, and 3:1 molar ratios of loratadine and citric acid. After solvent evaporation white, powdery systems were obtained. We also prepared mixtures in molar ratios 1:2, 1:3 loratadine, and citric acid, which remained semisolid after drying and had not been used. A 1:1 binary mixture presented a tendency to agglomerate after it was kept at room temperature and normal humidity so it had to be powdered and sieved before utilization (Figure 1). All samples were kept in a desiccator.

3.2. Characterization of Co-Amorphous Loratadine–Citric Acid System

3.2.1. DSC

Thermograms of loratadine, citric acid, and mixtures are shown in Figure 2. The sharp endothermic peak crystalline loratadine and citric acid at 136.98 °C and 156.4 °C, respectively, showed the melting point of the substances, in good agreement with their reported values [19,21,38,39]. DSC curves of binary mixtures exhibited the lack of endothermic peaks corresponding to melting points of loratadine and citric acid and were distinctly different from the crystalline pure components, suggesting the formation of a new phase.

3.2.2. FTIR

The FTIR spectra (Figure 3) of crystalline loratadine present characteristic peaks at 1701 cm⁻¹ for C=O stretching vibrations of ester, 1560–1554 cm⁻¹ stretching vibrations of the pyridine ring, and 1434 cm⁻¹ stretching vibrations of the benzene ring. Citric acid shows characteristic peaks at 3494 cm⁻¹ for O-H stretching vibrations, 1751 cm^−1, and 1704 cm⁻¹ C=O stretching for COOH groups. The spectra of binary mixture systems present the modification of the absorption peaks of the C=O stretching vibration of loratadine from 1701 cm⁻¹ to 1694 cm⁻¹ and the COOH groups of citric acid from 1751 cm⁻¹ to 1733 cm⁻¹. Our results were in accordance with the findings of Wang et al. [19].

FTIR was used to evaluate the newly formed non-covalent bonds between loratadine and citric acid after evaporation from ethanol. Hydrogen bonds appear on the spectra as shifts or broadening of the characteristic peaks of functional groups. The hypsochromic shifts of the C=O stretching vibration of the ester of loratadine and COOH groups of citric acid may indicate the forming of hydrogen bonds.

Solid state analysis indicates the formation of co-amorphous systems, the forming of a non-covalent bond between loratadine and citric acid.

3.2.3. Dissolution Test

The dissolution (Figure 4) of crystalline loratadine at each point of the dissolution curve is lower than the dissolution of the binary system. Binary mixtures at 2:1 and 3:1 ratios presented a lower dissolved amount of loratadine after 5 min compared to the 1:1 system, but after 60 min there was a three to four-fold increase in the dissolved amount of loratadine. The dissolution percentage of the co-amorphous system 1:1 at 60 min was a five-fold amount of pure loratadine (10% and 2.2%, respectively).

3.3. Evaluation of ODx

3.3.1. The Physical Appearance of ODx

Intact 10 mg loratadine tablets with a uniform white color, were obtained. No differences, except shape, regarding the physical appearance of the three formulations were observed for both preparation methods (Figure 5).

3.3.2. Diameter, Thickness, Hardness, Friability, Mass Uniformity, and Disintegration of ODx (Table 3)

Citric acid from the co-amorphous system in the composition of ODT serves as an aromatizing agent with a pleasant lemon taste, and mannitol and sorbitol have a sweet taste.

Table 3. Parameters of the ODx.

Tablets		Diameter (mm) ± SD	Thickness (mm) ± SD	Hardness (N) ± SD	Friability (%)	Mass Uniformity (mg) ± SD	Disintegration (s) ± SD
DC	1:1	9.068 ± 0.01	2.642 ± 0.01	38.14 ± 5.84	0.82	198.56 ± 3,49	34 ± 4.9
	2:1	9.013 ± 0.03	2.645 ± 0.02	47.86 ± 7.22	0.97	198.71 ± 2,98	36 ± 5.2
	3:1	9.006 ± 0.02	2.646 ± 0.02	46.14 ± 7.38	0.79	199.1 ± 2,44	41 ± 5.4
OL	1:1	-	3.448 ± 0.17	above 50	0.69	200.51 ± 4.40	8 ± 1.1
	2:1	-	3.452 ± 0.11	above 50	0.49	203.11 ± 4.64	9 ± 1.4
	3:1	-	3.471 ± 0.12	above 50	0.47	204.34 ± 4.75	8 ± 1.5

Table 3. Parameters of the ODx.

Tablets		Diameter (mm) ± SD	Thickness (mm) ± SD	Hardness (N) ± SD	Friability (%)	Mass Uniformity (mg) ± SD	Disintegration (s) ± SD
DC	1:1	9.068 ± 0.01	2.642 ± 0.01	38.14 ± 5.84	0.82	198.56 ± 3,49	34 ± 4.9
	2:1	9.013 ± 0.03	2.645 ± 0.02	47.86 ± 7.22	0.97	198.71 ± 2,98	36 ± 5.2
	3:1	9.006 ± 0.02	2.646 ± 0.02	46.14 ± 7.38	0.79	199.1 ± 2,44	41 ± 5.4
OL	1:1	-	3.448 ± 0.17	above 50	0.69	200.51 ± 4.40	8 ± 1.1
	2:1	-	3.452 ± 0.11	above 50	0.49	203.11 ± 4.64	9 ± 1.4
	3:1	-	3.471 ± 0.12	above 50	0.47	204.34 ± 4.75	8 ± 1.5

The diameter of direct compression ODx was about 9 mm. Very similar thickness and diameter values for direct compression ODx were measured, and for a given parameter there was no significant difference between the formulations (p > 0.05) values 0.888, 0.600, 0.532. In the case of freeze-dried ODx the change in thickness was higher, but less than 5% of the mean value. Friability was below 1% in all cases; lower values were measured for OL.

Disintegration time for DC ODx was above 30 s, but under 180 s and below 10 s for OL. Direct compression ODx with Kollidon CL as superdisintegrants were previously studied by Amelian et al. [29]. Our disintegration times with the co-amorphous loratadine citric acid system were very slightly above 30 s, and friability in both studies was under the acceptance limit of 1%, meaning tablets were nonfragile and could be easily handled.

Comparing the two preparation methods ODx friability and disintegration time presented differences. Disintegration was under 10 s for freeze drying explained probably by the porous structure of the tablets and the use of croscarmellose sodium, as superdisintegrants. A high gelatin concentration may result in a rigid three-dimensional network after lyophilization due to the presence of a high number of fibers forming cross-links and interchain H-bonds, causing the modification of mechanical properties [40,41].

Crosslinked polyvinylpyrrolidone in 5, 10, and 15% tablets obtained by direct compression results in hardness values under 25 N determined by Gupta [42]. In our cases, 5% Kollidon CL resulted in a higher resistance from 38 to 48 N.

OL was easily removed from the blister’s cavity without adhesion. Because of the weak adherence between the tablets and blister cavity, the OL has no or minimum movement in the pack indicating that it will be stable during transportation.

During hardness determination, freeze-dried tablets firstly were pressed to a more compact form by the tester and after then, breaking took place, resulting in higher resistance values.

Mass uniformity was within acceptable limits of the European Pharmacopeia. Higher mass variations were observed for OL, this difference was attributed to the difference in the technology used for manufacturing of ODx.

3.3.3. Dissolution in Simulated Stomach Fluid

In simulated stomach fluid, the dissolution of loratadine was almost complete after 30 min in all cases (Figure 6). At 15 min freeze-dried ODx presented above 90% of dissolved loratadine.

4. Conclusions

This study aimed at the preparation and characterization of co-amorphous loratadine–citric acid orally disintegrating dosage forms. DSC curves and FTIR spectra proved the formation of the co-amorphous system by hydrogen bonds. Dissolution studies indicated a five-fold increase in the dissolved amount compared to pure loratadine in water. ODx obtained by direct compression and lyophilization proved to have the adequate mechanical strength to withstand packing and manipulation. Dissolution studies of ODx for both preparation methods indicated above 93% of dissolved loratadine after 30 min. In conclusion binary systems of loratadine and citric acid enhance solubility and combined with the orally disintegrating pharmaceutical form, also increase patient compliance.