2024 Volume 72 Issue 7 Pages 681-688
Clarithromycin (CLA) is the preferred drug for treating respiratory infections in pediatric patients, but it has the drawbacks of extreme bitterness and poor water solubility. The purpose of this study was to improve solubility and mask the extreme bitterness of CLA. We use Hot Melt Extrusion (HME) to convert CLA and Eudragit® E100 into Solid Dispersion (SD). Differential scanning calorimetry (DSC) and Powder X-ray diffraction (PXRD) were used to identify the crystalline form of the prepared SDs, which showed that the crystalline CLA was converted to an amorphous form. At the same time, an increase in dissolution rate was observed, which is one of the properties of SD. The results showed that the prepared SD significantly increased the dissolution rate of crystalline CLA. Subsequently, the SD of CLA was prepared into a dry suspension with excellent suspending properties and a taste-masking effect. The bitterness bubble chart and taste radar chart showed that the SD achieved the bitter taste masking of CLA. Principal components analysis (PCA) of the data generated by the electronic tongue showed that the bitter taste of CLA was significantly suppressed using the polymer Eudragit® E100. Subsequently, a dry suspension was prepared from the SD of CLA. In conclusion, this work illustrated the importance of HME for preparing amorphous SD of CLA, which can solve the problems of bitterness-masking and poor solubility. It is also significant for the development of compliant pediatric formulations.
Clarithromycin (CLA) is a second-generation antibiotic drug in the macrolide class with superior pharmacological and significant antibacterial activity against common anaerobic bacteria.1,2) and is currently the drug of choice for pediatric respiratory tract infections. However, CLA has an extreme bitterness and poor water solubility (belonging to BCS II), limiting its widespread use in pediatric oral formulations.3–5) Currently, the clarithromycin preparations on the market are mainly available in tablet and capsule, which are not easy for children to swallow and carry the risk of asphyxiation by inhalation into the trachea.6) It has been shown that child-friendly dosage forms such as dry syrup formulation, granule, and dry suspension effectively improve the acceptance of medication in pediatric patients, thereby improving drug efficacy.7) Compared with standard tablets, dry suspensions have the advantages of both solid formulations, which are convenient to carry and stable, and liquid formulations, which are suitable to take. However, these dosage forms have high taste requirements, most drugs do not taste good, and children are more sensitive to the perception of bitterness than adults. Therefore, developing bitterness-masking techniques for drugs is significant for developing pediatric dosage forms.8)
As a result, pharmaceutical industries invest a great deal of money, time costs, and researchers into the development of potential technology for taste-masking,9) such as fluidized-bed coating10) ion exchange resin technique,11) supercritical fluids,12) and reverse micelles technique.13) However, these traditional techniques are time-consuming and expensive. Therefore, there is a need for a simple and efficient method to formulate compliant CLA formulations for children. Hot melt extrusion (HME) is a continuous process in which a mixture of powdered drug and excipient is mixed in a closed system at high temperature and pressure and conveyed by a screw.14) The unique advantages of HME are that (a) no organic solvent residue, environmentally friendly technology, (b) full compression in a relatively closed pipe to minimize oxygen leakage, and (c) HME can be adapted for continuous manufacturing and has a low production cost.15) Solid dispersions (SDs) have proven to be an effective technique for increasing the solubility of insoluble drugs, improving oral bioavailability, and simultaneously providing bitterness masking.16) It is based on the principle of uniformly dispersing active pharmaceutical ingredients (API) in a polymer to form an amorphous state that masks the bitterness of the drug. With the increasing progression of bitter medicines for children in recent years, HME is increasingly being applied in pharmaceutical formulations.17) HME technology has emerged over the last decade as a green18) continuous processable process for the development of SDs, playing an irreplaceable and vital role in the pharmaceutical industry.19)
HME can be used to conduct studies on bitter drug taste masking, and several studies have shown that when drug molecules are uniformly dispersed in an amorphous form in a taste-masking polymer7,16,20,21) taste masking can be achieved by preventing the bitter drug from coming into contact with the patient’s taste buds.9,13,22) Amin et al. successfully masked the bitter taste of azithromycin by applying HME to prepare SDs and effectively improved the solubility.3) It is worth mentioning that the hydrogen bonding forces generated between the drug molecules and the polymer matrix can overcome the undesirable taste of the drug. Gryczke et al.23) effectively improved the taste of ibuprofen by using a polymer with an opposite charge to the API so that intermolecular forces (hydrogen bonding) were formed between the two to achieve the bitter taste masking.11,24,25) Although HME is an effective technique to address the bitterness of drugs, the success of the final effect and the ability to improve patient compliance and palatability depends on developing an excellent and feasible prescription process.26,27)
Based on our knowledge, no pediatric CLA dry suspension formulation via HME is available on the market. Therefore, the objectives of the present study were to mask the bitter taste, enhance solubility of CLA using the HME technique, and optimize the HME processing conditions by orthogonal test. Crystalline characterization, prescription optimization, taste evaluation, in vitro dissolution, and other studies were carried out on the dry suspension formulation to provide the theoretical basis for its taste-masking potential.
HME process. Clarithromycin (CLA) was purchased from Shixing Pharmaceutical (China). Eudragit® E100 and Eudragit® EPO polymers were donated by Evonik Pharma Polymers (China). Crosslinked polyvinylpyrrolidone (PVP VA64) and Klucel™ HPC were also donated from Ashland. Soluplus was also donated by BASF (China). The HPLC solvents were of analytical grade and purchased from Fulltime Specialized Solvents (China). All materials were used as received.
Dry suspension preraration. Lactose, MCC-CMC-Na crosslinker, PVP K30, and MCC were purchased from Sunhere Pharmaceutical (China).
Preparation of SD via HMEHansen Solubility Parameter (HSP)HSP predicts the miscibility between different material systems by assessing the intermolecular forces between chemical structures. For HME research, it is commonly used to determine whether polymers and APIs are miscible. In general, when the HSP difference is <7 MPa0.5, it indicates that the drug and polymer are likely to be well miscible.28)
The HSP of CLA and some polymers is taken from the literature.
HME ProcessThe drug and the polymeric material were homogenized to obtain a physical mixture (PM). To find the best process to optimize CLA for preparing the best taste-masking formulation. Processing is carried out with a twin-screw rotary extruder (Thermo Fisher Scientific, China) at different screw speeds of 25–100 rpm in a temperature range of 130–220 °C.
Univariate and Orthogonal Array ExperimentalThe prescription was initially optimized by designing univariate experiments, followed by an orthogonal array experimental design to determine the optimal prescription. The interactions of the independent variables were investigated by selecting screw speed, processing temperature, and drug–polymer ratio as the independent variables and the taste-masking effect (dissolution of CLA in saliva) as the dependent variable. Finally, the interactions between the variables were assessed.
Physicochemical Characterization of SDThermogravimetric Analysis (TGA)The thermal characteristic of the drug is also an essential indicator in the processing of HME. TGA was conducted to research the material’s thermal stability using TGA Q50 (TA Instruments, U.S.A.). An appropriate sample (5–10 mg) was taken in an aluminum sample tray and heated from 30 to 600 °C at 10 °C/min in a dry nitrogen atmosphere. The mass loss of the sample was recorded.
Differential Scanning Calorimetry (DSC)DSC was applied for the study. A Q50 (TA Instruments) differential scanning calorimeter was used to examine the thermal properties of CLA, physical mixtures, and prepared extrudates. SD was treated in sealed aluminum pans (2–5 mg). SD was treated at 10 °C/min in a nitrogen atmosphere (from 30 to 250 °C). The samples were treated at 10 °C/min in a nitrogen atmosphere.
Powder X-ray Diffraction (PXRD)The PXRD analysis of API, Eudragit® E100, PM, and SD was done using an X-ray diffractometer (Rigaku, Japan). Data was collected within 2θ = 5–50°, keeping the step size 0.02°.
Fourier Transform IR Spectroscopy (FTIR)The API, Eudragit® E100, and SD were analyzed via FTIR 8400 S (Thermo Fisher Scientific, U.S.A.). After drying, the samples were blended with KBr in a mortar and pestle, ground to a homogeneous powder, and pressed under pressure into 5 mm flakes. FTIR spectrum was recorded within 4000–500 cm−1.
Scanning Electron Microscope (SEM)CLA, PM, and SD appearances were investigated using SEM (Hitachi, Japan). Research was carried out using secondary imaging techniques at different magnifications. The analysis was performed at an accelerating voltage of 30 kV.
Preparation of Dry SuspensionsPass all the excipients through 100 mesh sieves, add an appropriate amount of water to make soft material, then add SD to the soft material, mix, pass through 30 mesh sieves, and dry at 60 °C for one hour.
Taste-Masking EvaluationBitterness evaluation is a crucial indicator in the evaluation of taste-masking prescriptions, and the most scientific and commonly used methods are in vitro dissolution experiments and electronic tongue. The in vitro dissolution test, which examines the taste-masking effect according to the dissolution of the drug within five minutes in the saliva environment, can be used to screen many prescriptions quickly. The electronic tongue method has the advantage of high sensitivity and reproducibility, which can evaluate the bitter taste observably, quickly, and accurately.
The experiments were performed using a taste analysis system from INSENT, Japan, model: SA402B. The device uses artificial lipid membrane sensors with wide-area selective specificity to mimic the taste perception mechanism of living organisms. According to Weber–Fechner law, the magnitude of the difference threshold is proportional to the strength of the standard stimulus for similar stimuli. Generally speaking, the human tongue can recognize the difference when the intensity of the taste substance changes by 20%. The electronic tongue defines a 20% change in the intensity of a flavor substance as a unit for taste measurement.
CLA Dry Suspension Quality EvaluationThe excellent suspension was stored and then oscillated, and the residue should be able to be re-dispersed rapidly. An orthogonal test examined the nature of suspension, and the type and dosage of excipients were determined preliminarily. Three batches of dry suspension were prepared for content assay according to the best method screened, and the dissolution was examined in comparison with the commercially available tablet of CLA.
For the dissolution test of CLA SD dry suspension, the dissolution medium was acetate buffer solution with pH 4.5 to simulate the intestinal environment, the volume of the medium was 900 mL, the speed of the dissolution instrument was 50 rpm, and the temperature was set at 37 ± 0.5 °C. Five milliliters of samples were taken at 5, 10, 20, 30, 45, and 60 min, respectively, and the samples were filtered through 0.45 µm membranes, and the filtrates were discarded. The sample was injected into 20 µL of HPLC, and the peak area was substituted into the dissolution curve.
In the HME process, polymer selection requires an assessment of the suitability of the formulation. HSP is an important parameter that describes the chemical structure of a molecule and is often used to understand the miscibility of the drug with a polymer. The HSPs of various materials are shown in Table 1. The HSP discrepancy (∆δ) between CLA and PVP VA64, HPC, Eudragit® EPO, Soluplus, and Eudragit® E100 are all less than seven, which indicates their good miscibility with CLA. Eventually, we selected these five materials to prepare CLA-SD.
In this study, CLA-Eudragit® E (Eudragit® E100 and Eudragit® EPO) particles showed less drug dissolution during the dissolution time interval than the other samples in Fig. 1A. The lower the drug release in the saliva system in the CLA formulation of HME particles, the higher the efficiency of the polymer in masking the taste, proving that Eudragit® E is a promising candidate for developing taste-masking formulations for HME. Eudragit® E is an excellent pH-sensitive taste-masking carrier, which is soluble below pH 5 and film-forming above pH 5. The difference between Eudragit® E100 and Eudragit® EPO lies in the particle size; Eudragit® EPO is micronized and commonly used for coating in formulations, and also offers numerous advantages in terms of processability and fast dissolution.
However, Eudragit® EPO is 3–4 times more expensive than Eudragit® E100. As can be seen in Fig. 1A, SDs prepared with Eudragit® E100 and Eudragit® EPO have virtually the same taste-masking effect. In practical pharmaceutical processing, mass production is one of the advantages of HME technology. Therefore, the polymer Eudragit® E100, which has a taste-masking effect and significant cost advantages, is selected to prepare the CLA-SD. The appearance of CLA-Eudragit® E100 particles at extrusion temperature is shown in Fig. 1B.
Preparation of Taste-Masked CLA Amorphous SDExtrusion TemperatureIn general, the higher the temperature, the higher the thermal energy absorbed during the extrusion process, which is more conducive to achieving the breaking of the lattice energy between the drug and the carrier into the amorphous form. However, it should be considered that temperatures that are too high may also degrade the drug and the carrier and produce by-products. Initially, the screw speed was set at 50 rpm and the drug–polymer ratio at 1 : 2 to investigate the effect of different extrusion temperatures on the taste-masking effect of SDs. As shown in Fig. 2A, the dissolution of the resulting extrusion is highest at a lower temperature of 130 °C. This may be related to the inability of CLA to disperse uniformly with the carrier at lower temperatures. However, when the temperature reaches 180 °C, the increased temperature will improve the dissolution and reduce the taste-masking effect. Therefore, the barrel temperature is set in the range of around 160 °C.
The delivery speed and residence time of the material in the barrel are closely related to the screw speed. When the screw rotates too slowly, the material has a longer residence time in the barrel and can absorb the heat more fully, but the low-speed results in less mechanical energy being input. At the same time, a residence time that is too long for heat-sensitive materials may lead to their degradation. If the screw speed is too fast, although the mechanical energy input is increased, the drug may not be sufficiently melted and well mixed.
After the previous experiment, we set the extrusion temperature to 160 °C and the drug–polymer ratio to 1 : 2 in order to investigate the effect of different screw speeds on the taste-masking effect of SDs. It can be seen from Fig. 2B that the screw speed is 75 rpm, and the dissolution in a salivary environment is the lowest, indicating a better taste-masking effect. Therefore, the screw speed is set in the range around 75 rpm.
Drug–Polymer RatioThe amount of polymer is crucial for the formation of SD. The right ratio facilitates a more homogeneous mixing of the drug with the polymer and stabilizes the amorphous form of the drug molecules. The temperature was set at 160 °C and the screw speed at 75 rpm to investigate the effect of different drug–polymer ratio on the extrusion process. It can be noted from Fig. 2C that when the ratio is 1 : 1, CLA is released the least, which proves that the bitter taste masking effect is good, and the increase or decrease of the proportion of CLA will reduce the masking effect. Therefore, the drug–polymer ratio is set in the range around 1 : 1.
Orthogonal Array Experimental DesignIt can be noted from Tables 2 and 3 that the dissolution of simulated saliva fluid is taken as a quantitative index. ANOVA results show that the sequence of various factors influencing the cumulative dissolution of CLA is A > C > B; that is, significant factors affecting the dissolution of CLA are the drug loading rate, processing temperature, and screw speed (Supplementary Table S1). All factors have an effect, but the magnitude of the impact varies. The optimal process combination is A1B2C3. The barrel temperature was 150 °C, the screw speed was 75 rpm, and the ratio of CLA to carrier Eudragit® E100 was 1 : 1.5. To ensure the homogeneity of the prescription extrusion, we added 3% Compritol® 888 as a plasticizer to the prescription to improve the compressibility.
| A | B | C | D | |
|---|---|---|---|---|
| Temperature (°C) | Screw Speed (rpm) | Mass Ratio | Blank | |
| 1 | 150 | 65 | 1.5 : 1 | 0 |
| 2 | 160 | 75 | 1 : 1 | 0 |
| 3 | 170 | 85 | 1 : 1.5 | 0 |
| Run sequence | A | B | C | D | Drug dissolution |
|---|---|---|---|---|---|
| 1 | 1 | 1 | 1 | 1 | 14.7 |
| 2 | 1 | 2 | 2 | 2 | 11.8 |
| 3 | 1 | 3 | 3 | 3 | 10.9 |
| 4 | 2 | 1 | 2 | 3 | 17.4 |
| 5 | 2 | 2 | 3 | 1 | 13.1 |
| 6 | 2 | 3 | 1 | 2 | 15.8 |
| 7 | 3 | 1 | 3 | 2 | 15.5 |
| 8 | 3 | 2 | 1 | 3 | 15.9 |
| 9 | 3 | 3 | 2 | 1 | 14.6 |
| K1 | 37.40 | 47.60 | 46.40 | 42.40 | |
| K2 | 46.30 | 40.80 | 43.80 | 43.10 | |
| K3 | 46.00 | 41.30 | 39.50 | 44.20 | |
| k1 | 12.47 | 15.87 | 15.47 | 14.13 | |
| k2 | 15.43 | 13.60 | 14.60 | 14.37 | |
| k3 | 15.33 | 13.77 | 13.17 | 14.73 | |
| R | 2.97 | 2.27 | 2.30 | 0.60 | A > C > B > D |
The thermal stability of the drug and polymer needs to be considered before the HME process to avoid drug degradation during processing. Therefore, a TGA analysis was performed on CLA and Eudragit® E100, shown in Fig. 3A. The CLA in the TGA curve offers a significant thermal event at around 250 °C, caused by drug degradation. The processing temperature of this experiment is below the decomposition temperature, and it can be considered that there will be no degradation of the drug during the extrusion process.
B) DSC Curves of CLA, PM, SD, and Eudragit® E100. C) PXRD Patterns of CLA, PM, SD, and Eudragit® E100. D) FTIR Spectra of CLA, PM, SD, and Eudragit® E100. E–G) SEM images of E) CLA, F) PM, G) SD. Scale bar, 50 µm.
The DSC temperature image shows CLA in Fig. 3B, which shows the sharp heat absorption peak at 229 °C, which indicates the drug’s melting point. The presence of this peak indicates that CLA is crystalline. For PM, the characteristic peak intensity of the drug is weakened, which suggests a decrease in the crystallinity of the drug.
The absence of a melting point peak of CLA in the resulting extrusion indicates no crystalline CLA in the extrudate. This is because the crystalline CLA has been treated in the high temperature and pressure environment of HME, which breaks the lattice energy of the drug and transforms it into an amorphous form.
PXRDPXRD studies were carried out on the crystalline state of CLA and the powders of each group of samples. The PXRD pattern of CLA (Fig. 3C) proved the crystalline nature of the drug due to the discovery of exclusive heat absorption peaks consistent with the literature.34) No distinctive peaks were observed for Eudragit® E100, thus confirming its amorphous nature.35) The PM peaks correspond to the characteristic peaks of CLA, but the intensity of some peaks is weakened. From the PXRD spectra, it can be found that the intensity of all the character peaks of SD has decreased, and the peak shape has become smooth from sharp, which indicates a decrease in its crystalline properties and proves Tantishaiyakul previously observed the transition from crystalline to amorphous forms similar behavior.36)
Fourier Transform IR (FTIR)FTIR analysis is conducted to analyze drug–polymer interactions, which usually result in shifting or disappearance/appearance of absorption peaks. The FTIR spectrum of CLA explained the representative band of hydrogen bonds between −OH groups vibration at 3466 cm−1, The O–C=O of the lactone ring is a stretching vibration at 1733 cm−1, the N-CH3 of the aromatic ring is stretched at 1424 cm−1, and the alkyl-CH3 substitution band is at 2940 cm−1.37) The FTIR spectra of SD showed all the characteristic peaks of the CLA and the polymer, but the hydroxyl peak disappeared in the SD, suggesting a possible hydrogen bonding interaction between the hydroxyl group of the dispersed CLA and the ester bond of the carrier. The interaction between the carrier and the drug is believed to play a crucial role in inhibiting recrystallisation of amorphous drugs. The addition of carriers may inhibit the binding of drug molecules to form nuclei and inhibit crystal growth.38)
SEMThe SEM graphics of CLA, PM, and SD are shown in Figs. 3E–G. The SEM images of CLA and PM demonstrated rough surface morphology. On the contrary, the SD showed homogeneously dispersed drug particles with smooth morphology. This indicates that CLA was uniformly distributed in the polymer carrier under suitable extrusion conditions. These findings are common, as previous studies have discovered comparable results.39)
Preparation of Dry SuspensionsFirstly, the types of suspending agents, binding agent, disintegrating agent, and their dosages were screened by pre-experiment. The prescriptions were further optimized using orthogonal tests to examine the dispersion properties of the prepared dry suspensions (Supplementary Tables S2, S3). The prescription of CLA SD dry suspension was finalized: milled lactose 50%, MCC-CMC-Na crosslinker 20%, CLA SD 19%, PVP K30 2%, MCC 5%, and corrective agent (menthol and sucralose) 4%. (Each 2 g packet contains 125 mg of CLA).
Taste-Masking EvaluationIn-vitro Drug Release StudiesTo assess the bitter masking effect of dry suspensions prepared by the HME process, we examined the in vitro dissolution of SD granules and dry suspensions (GHX) containing 450 mg of CLA equivalents in comparison with physical mixtures (same API concentration) and the dissolution analysis is shown in Fig. 4A. Lower dissolution of SD with GHX in the salivary environment compared to CLA and PM. This result shows that after using HME to prepare SD, the dissolution of CLA decreased in the saliva environment, which proved that SD has a taste-masking effect. According to International Pharmaceutical Federation guidelines, dissolution values can be used to determine the approximate baseline for bitterness.40) Researchers have previously used in vitro dissolution studies to evaluate the bitterness of Griseofulvin and Caffeine Anhydrous by HME.41)
B) The electronic tongue tastes radar chart. Aftertaste-A is the aftertaste of astringency; Aftertaste-B is the Aftertaste of Bitterness. H-bitterness is the bitterness of hydrochloride, and B-bitterness is the bitterness of the drug base. C) Bitterness bubble map (Bitterness is acidic bitterness, B-bitterness2 is base bitterness, H-bitterness is hydrochloride bitterness). D) Results of principal component analysis (PCA) of samples.
In this study, SD was significantly reduced in dissolution compared to CLA, indicating a reduced drug release in the saliva environment in Fig. 4A. The lower the release of SD drugs prepared by HME, the better the taste-masking efficiency, which makes Eudragit® E100 an essential polymer for HME to develop taste-mask formulations. In another study by Maniruzzaman and colleagues, oral taste-masking preparations of paracetamol via HME were evaluated using dissolution studies as taste-masking evaluations and compared with electronic tongue results, and the two evaluation methods ultimately reached consistent conclusions.42)
There is a correlation between the dissolution and e-tongue studies for bitter taste detection. There is a good relationship between lower drug release and taste-masking effect in the dissolution test. Due to its objective and accurate nature, electronic tongue probing has always been an effective tool for assessing the efficiency of bitter taste masking formulations. Therefore, we investigated the subsequent electronic tongue evaluation of taste masking samples to obtain a genuinely objective taste masking effect.
INSENT Electronic TongueThe electronic tongue (e-tongue) has the advantage of accuracy and intuitive data results, so we used it to evaluate the taste masking effect.43) Other researchers have conducted similar studies where products were subjected to PCA to assess the taste-masking efficacy of different types of samples.21) For research purposes, CLA, PM, SD, and GHX were handled according to the methodology described in the previous section. Based on the projections derived from PCA, the signals of the various formulations were represented on the taste map, as shown in Fig. 4B. The information on the graph shows the relative distribution and proximity of the bitterness of each sample. The result shows a significant difference in distance and bitterness of HME-processed SD compared to API. In addition, the taste map shows a clear difference between SD and CLA. PM and CLA are close, while SD is relatively far away. This implies a significant improvement in the bitter taste after HME treatment, and the prepared SD has a significant bitterness-masking effect compared to the CLA before treatment.
In Fig. 4C, the greater the value of the test, the heavier the bitterness, and it can be seen in the radar chart that CLA and PM have the heaviest bitterness, while SD and GHX prepared by HME have the lowest bitter value, indicating that the masking effect is noticeable. The bitterness bubble chart (Fig. 4D) shows that SD and GHX effectively mask various bitterness of CLA, including acidic bitterness, base bitterness, and hydrochloride bitterness. In vitro evaluation of the electronic tongue is highly consistent with in vitro dissolution test results, demonstrating that the e-tongue is an effective tool for determining optimal taste-masking formulations. Sensor details and test data are shown in Supplementary Tables S4 and S5. This approach can more accurately help researchers understand the taste profile of a product.
CLA Dry Suspension Quality EvaluationThe optimum prescription was determined by designing an experimental orthogonal array design. Finally, the dry suspension was quality tested to examine the appearance, settling properties, content, and dissolution comparison with commercially available tablets.
The prepared dry suspension had uniform white particles that had a neat appearance and no impurities on the surface. (Fig. 5A), The content of three batches of CLA SD dry suspension was determined, and the average content was 93.04% with an RSD of 1.5% (Supplementary Table S6). According to the Chinese Pharmacopoeia, the content determination should be 90.0 to 110.0% of the labeled amount, and the content uniformity meets the requirements. The prepared suspensions had excellent settling properties, were shaken well after storage, were free from delamination and aggregation, and could rapidly redisperse. The results are shown in Supplementary Table S7.
The dissolution results of homemade CLA SD dry suspension compared with commercially available tablets are shown in Fig. 5B. At pH 4.5, the reference table and dry suspension (GHX) were released entirely within 5 min. The dissolution reached 104.20 and 106.50% at 60 min. Due to its pH-dependent solubility (dissolved at pH <5.0), the GHX and SD, essentially insoluble in the salivary environment, dissolve rapidly at pH 4.5.
The dissolution results are shown in Fig. 5B. The dissolution profile of SD was significantly higher than that of pure CLA. SD was almost completely dissolved within 10 min and reached a steady state with complete release of CLA within 30 min, whereas the cumulative dissolution of pure CLA was only close to 60% within 60 min, indicating that the prepared SD significantly enhanced the dissolution rate of crystalline CLA. This result was attributed to the fact that the drug molecules were dispersed in the carrier in an amorphous state, proving that the prepared SD successfully enhanced its aqueous solubility while masking its bitter taste.
In this study, the innovative use of HME technology to combine Eudragit® E100 with CLA to prepare SDs solved the limitations of bitterness and poor solubility. The crystal-shaped CLA shifted to an amorphous state after HME processing and interaction with the material Eudragit® E100 material. Process conditions play a decisive part in the technique’s effectiveness, and the optimal process prescription was worked out through univariate and orthogonal experimental design. In conclusion, Taste-masking solid dispersible dry suspensions prepared by HME technology are easy to process and improve pediatric patients’ compliance. Its advantage lies in effectively masking the bitter taste while enhancing the water solubility of insoluble drugs. Its theoretical research has matured, providing essential guidance for the large-scale production of taste-masking formulations. Currently, there are no marketed pediatric dosage forms of CLA dry suspension via SDs, making this study pioneering.
The authors thank the Key Technology Research and Industrialization Demonstration Projects of Qingdao.
This research was partially funded by the Industrialization Demonstration Projects of Qingdao (22-3-3-hygg-25-hy).
Tianao Zhang: Investigation, Data curation, Resources, Writing. Min Yu: Investigation. Yong Fan: Investigation. Lingyang Wang: Methodology. Lu Yuan: Investigation. Yong Sun: Methodology, Supervision, Resources, Review & Editing.
The authors declare no conflict of interest.
Data will be made available on request.
This article contains supplementary materials.
