A method for analyzing the distribution of an API in a semi-solid formulation and the binding mode of the API to excipients

Abstract

The application relates to an analysis method for API distribution form in a semi-solid preparation and a combination mode of the API and accessories, which comprises the following steps: obtaining a raw material medicine and accessory fingerprint peaks; loading the semi-solid preparation into an in-situ chip; magnifying and splicing a to-be-measured sample area in the in-situ chip, observing whether there are particles or oil drops, screening and splicing the particles if the particles exist, collecting fingerprint peaks of the particles to confirm the components of the particles, finding API in the particles, and determining that the API at least partially exists in the form of particles, finding no API in the particles, and determining that the API exists in a dissolved form, imaging the to-be-measured sample area where the particles exist by using a Raman spectrometer, imaging any to-be-measured sample area by using the Raman spectrometer if there are no particles and oil drops, imaging the oil drops by using the Raman spectrometer if there are no particles but there are oil drops, and finally confirming the API distribution and the combination mode of the API and the accessories. The analysis method has the advantages of high efficiency and high precision, and has a wide application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical testing and analysis technology, specifically relating to an analytical method for the distribution of APIs in semi-solid preparations and their binding with excipients. Background Technology

[0002] Raman spectroscopy, as a non-destructive analytical technique, has been widely used in many fields such as materials science, chemistry, and biology. Its principle is based on molecular scattering. When monochromatic light (such as laser light) shines on a sample, most of the light is scattered in the direction of incidence, i.e., Rayleigh scattering; while a small portion of the light is scattered in different directions and frequencies, i.e., Raman scattering. The frequency variation of Raman scattered light is closely related to the vibrational and rotational energy levels of the sample molecules, thus providing detailed information about the molecular structure and chemical bonds of the sample.

[0003] For the detection of semi-solid dosage forms, traditional methods mainly involve directly applying the semi-solid formulation to a glass slide for detection. Since some components in semi-solid formulations may be volatile, direct exposure to air leads to the loss of these components' volatility. This loss of volatility not only alters the sample composition but may also trigger internal chemical reactions, causing sample deterioration and affecting the accuracy of the detection results. Some researchers have used coverslips to cover the glass slides coated with the semi-solid formulation to prevent direct exposure and deterioration. However, this method still has many problems, such as: the coverslip can crush large particles in the semi-solid formulation, thus obscuring its true morphology and making it impossible to accurately detect the binding mode of APIs and excipients. Furthermore, the sealing effect between the coverslip and the glass slide is not ideal, and the sample still carries the risk of deterioration. In addition, traditional Raman spectroscopy analysis has a significant drawback in sample component detection: its slow detection speed.

[0004] Therefore, it is of great significance to develop an analytical method that can rapidly and accurately detect the distribution of APIs and their binding with excipients in semi-solid dosage forms. Summary of the Invention

[0005] The purpose of this invention is to provide an analytical method for the distribution of APIs and their binding with excipients in semi-solid preparations. This analytical method is efficient, accurate and reliable.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: This invention provides an analytical method for the distribution pattern of APIs and their binding mode with excipients in semi-solid dosage forms, wherein the semi-solid dosage forms consist of active pharmaceutical ingredients (APIs) and excipients, and the analytical method includes: (1) Use a Raman spectrometer to obtain the fingerprint peaks of the active pharmaceutical ingredient and the excipients and confirm the difference peaks; (2) Load the semi-solid preparation into an in-situ chip, the in-situ chip including an in-situ chip body and a cover glass adapted to the in-situ chip body, the in-situ chip body having an inwardly recessed groove (specifically formed by laser processing or etching), the loading specifically includes delivering the semi-solid preparation into the groove, then covering the in-situ chip body with the cover glass and completely covering the groove, and finally sealing the periphery of the cover glass with the in-situ chip body using sealant; (3) Use a microscope to magnify the sample area to be tested in the in-situ chip by a preset magnification and stitch them together to obtain a large area. Observe whether there are particles or oil droplets in the sample area to be tested. If there are particles, proceed to step (4). If there are no particles or oil droplets, proceed to step (5). If there are no particles but there are oil droplets, proceed to step (6). (4) First, use an optical microscope to screen the observed particles and splice the areas where the screened particles are located. Then, use a Raman spectrometer to collect the fingerprint peaks of the particles. Compare the collected fingerprint peaks with the fingerprint peaks of the active pharmaceutical ingredient and excipients in step (1) to analyze the composition of the particles. If the particles contain the active pharmaceutical ingredient, confirm that the API in the semi-solid preparation is at least partially distributed in particulate form (including both particulate form and partly dissolved form) and confirm its crystal form. If the particles do not contain the active pharmaceutical ingredient, confirm that the API in the semi-solid preparation is distributed in dissolved form. Use a Raman spectrometer to image the sample area where the particles are located to confirm the binding mode of the API and excipients in the semi-solid preparation. (5) Use a Raman spectrometer to image any region of the sample to be tested to confirm the distribution of APIs in the semi-solid formulation and their binding mode with excipients; (6) The oil droplets were imaged using a Raman spectrometer to confirm the distribution of APIs in the semi-solid formulation and their binding with excipients.

[0007] The applicant optimized the design of the in-situ chip, loading the semi-solid formulation into the groove of the in-situ chip, and using sealant to seal the in-situ chip body and coverslip. This prevents the loss of volatile components in the semi-solid formulation and avoids the impact of internal oil droplet or particle aggregation on the test results, ensuring the stability and integrity of the sample during the detection process. Furthermore, the groove depth of the in-situ chip can be flexibly designed to precisely accommodate droplets of different sizes. Specifically, the loading process may include the following steps: first, the semi-solid formulation is placed in the groove of a certain in-situ chip; the formulation is observed under a microscope; the appropriate groove depth is determined based on the largest diameter particle or oil droplet; and the corresponding in-situ chip is selected for subsequent loading. If no particles or oil droplets are present in the formulation, the in-situ chip can be selectively replaced or not, and then sealed with sealant to complete the entire loading process. Its design avoids both the crushing of droplets due to insufficient groove depth and the inability to effectively restrict the inherent Brownian motion of small droplets due to excessive groove depth, thus preventing sample movement and displacement from the observation field during testing. This ensures the true morphology of the sample and enables stable testing over a long period, resulting in more accurate and reliable test results. Furthermore, the applicant uses a microscope to stitch and screen the sample area under test, and collects fingerprint peaks from the screened particles. Compared to traditional collection methods, this approach allows for a larger sample volume and higher efficiency.

[0008] Preferably, the imaging area in steps (4) and (6) is twice or more the area of ​​any observed particle or oil droplet.

[0009] More preferably, the imaging area in steps (4) and (6) is 2 to 5 times the area of ​​any observed particle or oil droplet.

[0010] Preferably, the in-situ chip body further has a fixing region, which is located on the bottom wall of the groove and recessed inward. The fixing region can more stably fix the emulsion droplets.

[0011] More preferably, the fixing region has multiple regions. The sum of the depth of the groove and the depth of the fixing region is configured to be 100%~110% of the maximum diameter of the particles or oil droplets in the semi-solid formulation. If the groove and fixing region are too deep, the sample will flow, affecting the test results. If the groove and fixing region are too shallow, large particles or oil droplets in the sample will be crushed during the sealing process, affecting the test results. Therefore, the above range is preferred. Further, the size of the fixing region is configured to constrain the particles or oil droplets in the semi-solid formulation, restricting the movement of the particles or oil droplets within the fixing region. As an example, the maximum inscribed circle diameter of the fixing region in a section perpendicular to its axial direction is D1, the semi-solid formulation contains particles or oil droplets with a maximum diameter of D2, and satisfies: D1 ≤ 1.1 × D2.

[0012] Preferably, the cover glass is made of calcium fluoride. Calcium fluoride cover glass has a higher laser transmittance, typically exceeding 95%, which helps improve detection accuracy.

[0013] Preferably, the preset magnification factor in step (3) is 5 to 100 times, for example, 5 times, 10 times, 20 times, etc.

[0014] Preferably, the semi-solid formulation is selected from any one of suspension formulations, gel formulations, and cream formulations.

[0015] In some embodiments, the cream formulation includes any one of mometasone furoate cream, imiquimod cream, and mupirocin ointment.

[0016] Preferably, the loading process further includes applying a semi-solid formulation to the grooves of the in-situ chip using a dropper or toothpick.

[0017] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art: The analytical method for the distribution of APIs and their binding with excipients in semi-solid preparations provided by this invention has the advantages of high efficiency and high accuracy, and has broad application prospects. Attached Figure Description

[0018] Figure 1 This is a schematic diagram of an in-situ chip structure provided by the present invention; Figure 2 This is a schematic diagram of an in-situ chip structure from another angle provided by the present invention; Figure 3 The Raman spectra of the active pharmaceutical ingredient and excipients in Example 1 are shown below. Figure 4 Microscopic image of the semi-solid formulation of Example 1; Figure 5 A polarized light microscope image of the semi-solid formulation of Example 1; Figure 6 This is a fingerprint peak acquisition diagram of the particles of the semi-solid formulation in Example 1; Figure 7 Another microscopic image of the semi-solid formulation of Example 1; Figure 8 for Figure 7 Raman spectral imaging distribution of the region shown in the red box; Figure 9 for Figure 7 Raman spectrum of the region shown in the red box; Figure 10 The Raman spectra of the active pharmaceutical ingredient and excipients in Example 2 are shown below. Figure 11Microscopic image of the semi-solid formulation of Example 2; Figure 12 A polarized light microscope image of the semi-solid formulation of Example 2; Figure 13 This is a fingerprint peak acquisition diagram of the particles of the semi-solid formulation in Example 2; Figure 14 The Raman spectra of the active pharmaceutical ingredient and excipients in Example 3 are shown below. Figure 15 Microscopic image of the semi-solid formulation of Example 3; Figure 16 A polarized light microscope image of the semi-solid formulation of Example 3; Figure 17 This is a fingerprint peak acquisition diagram of the particles of the semi-solid formulation in Example 3; Figure 18 Another microscopic image of the semi-solid formulation of Example 3; Figure 19 for Figure 18 Raman spectral imaging distribution of the region shown in the red box; Figure 20 for Figure 18 Raman spectrum of the region shown in the red box; Figure 21 Microscopic image of progesterone in an in situ chip; Figure 22 Another microscopic image of progesterone in an in situ chip; Figure 23 Microscopic image of progesterone on a regular glass slide; Figure 24 Another microscopic image of progesterone on a regular glass slide; Figure 25 Raman spectra of formulations in situ on a chip and formulations on a regular glass slide; Among them, 1. In-situ chip body; 11. Groove; 2. Cover glass. Detailed Implementation

[0019] The present invention will be further described below with reference to embodiments. However, the present invention is not limited to the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to different requirements of specific applications, and the implementation conditions not specified are conventional conditions in the industry. The technical features involved in the various embodiments of the present invention can be combined with each other as long as they do not conflict with each other.

[0020] In the following examples and comparative examples, the raw materials and instruments used are all commercially available products.

[0021] Unless otherwise specified below, the in-situ chip used includes the in-situ chip body 1 and the cover glass 2. Figure 1As shown, the in-situ chip body 1 has a groove 11 in the middle region. The depth of the groove 11 can be designed according to actual needs, preferably 100%~110% of the maximum diameter of particles or oil droplets in the formulation, to ensure that particles in the formulation do not agglomerate and oil droplets do not move. In other embodiments, the in-situ chip body 1 also has a fixing region, which is located on the bottom wall of the groove 11 and recessed inward, for more stable fixation of the formulation. A coverslip 2 is placed on the groove 11 and its area is larger than the groove opening area of ​​the groove 11 to completely cover the groove 11. Preferably, the coverslip 2 protrudes outside the groove 11 on all sides and can be tightly adhered to the slide body 1 by resin adhesive, thereby preventing the formulation from evaporating. The coverslip 2 is made of calcium fluoride and has a thickness of 0.5mm~1mm. The resin adhesive is a conventional sealant in the art and is not specifically limited.

[0022] Example 1: Analysis of the existing forms of API (mometasone furoate cream) and its binding with excipients, including the following steps: Step 1: Collect fingerprint peaks of the active pharmaceutical ingredient (API) and excipients separately, and identify the difference peaks to distinguish the API from the excipients in the formulation. This involves taking a small amount (using a toothpick to apply a small amount) of the API (mometasone furoate) and excipients (white petrolatum; white beeswax; hexanediol; titanium dioxide; phosphoric acid; aluminum starch octenyl succinate; hydrogenated soybean lecithin) and spreading them on a commercially available ordinary glass slide. Then, flatten the slide with a coverslip and collect the fingerprint peaks sequentially using a Raman spectrometer (Witec, model 300R). The excitation wavelength was 532 nm, and the spectral acquisition range was 200-4000 cm⁻¹. -1 See Table 1 for API and excipient characteristic peaks. Figure 2 .

[0023] Table 1

[0024] Step 2: After ultrasonically cleaning the in-situ chip body and coverslip for 5 minutes, use tweezers to place them in an oven to dry, then remove them and place them on the sample preparation table for later use. Use a toothpick to apply the test reagent (mometasone furoate cream, brand: Elocon) into the in-situ chip groove. Use tweezers to gently pick up the coverslip and place it on the in-situ chip body, completely covering the groove. Seal the edges of the coverslip with resin adhesive.

[0025] Step 3: Using a microscope, the area of ​​the test formulation within the in-situ chip recess is pieced together into a larger area at low magnification (10X), such as... Figure 3 As shown, observe whether there are particles in the sample. Figure 3 The presence of particles indicates that their composition needs to be confirmed.

[0026] Step 4: The particles observed in Step 3 are screened using a polarizing microscope and the regions are then pieced together, such as... Figure 4 As shown. Simultaneously, Raman spectroscopy was used to collect fingerprint peaks of the particles to confirm their composition, such as... Figure 5 As shown, the particles mainly consist of white petrolatum, titanium dioxide, aluminum starch octenyl succinate, and other excipients, with no obvious API signal detected. (During automatic statistics, the particles are simulated as rectangular sampling centers; when the particle morphology is irregular, the matrix will be sampled.) Step 5: Based on the above results, no API was found in the particles. Subsequently, Raman spectroscopy imaging was performed on the formulation area (the imaging area should be at least twice the size of the particles within the formulation). Figure 6 The area within the red box in the middle, Figure 7 For the imaging distribution map, Figure 8 The fingerprint peak diagram for the region.

[0027] Conclusion: The API in the formulation is distributed in hexanediol in a dissolved form.

[0028] Example 2: Analysis of API (imiquimod cream) distribution / crystal form, including: Step 1: Collect fingerprint peaks for the active pharmaceutical ingredient (API) and excipients separately, and identify the difference peaks to distinguish the API from the excipients in the formulation. This involves taking small amounts of the API (imiquimod) and excipients (glycerin; methylparaben; propylparaben; liquid paraffin; white petrolatum; cetyl alcohol; cetearyl alcohol) and spreading them on commercially available ordinary glass slides, then pressing them flat with a coverslip. Fingerprint peaks are then collected sequentially using a Raman spectrometer. The excitation wavelength is 532 nm, and the spectral acquisition range is 200-4000 cm⁻¹. -1 See Table 2 for characteristic peaks of API and excipients. Figure 9 .

[0029] Table 2

[0030] Step 2: After ultrasonically cleaning the in-situ chip body and coverslip for 5 minutes, use tweezers to place them in an oven to dry, then remove them and place them on the sample preparation table for later use. Use a toothpick to apply the test reagent (imiquimod cream, brand: Licojie) into the in-situ chip groove. Use tweezers to gently pick up the coverslip and place it on the in-situ chip body, completely covering the groove. Seal the edges of the coverslip with resin adhesive.

[0031] Step 3: Using a microscope, the area of ​​the test formulation within the in-situ chip recess is pieced together into a larger area at low magnification (10X), such as... Figure 10 As shown, observe whether there are particles in the sample. Figure 10 The presence of particles indicates that their composition needs to be confirmed.

[0032] Step 4: The particles observed in Step 3 are screened using a polarizing microscope and the regions are then pieced together, such as... Figure 11As shown. Simultaneously, Raman spectroscopy was used to collect fingerprint peaks of the particles to confirm their composition. Figure 12 It can be seen that a clear API signal was found, and the API has two crystal forms (API-1 is consistent with the crystal form of the active pharmaceutical ingredient, and API-2 is the API after crystal transformation); (yezhuanshila and baifanshilin are excipients; during automatic statistics, the particles are simulated as rectangular collection centers. When the particle morphology is irregular, the matrix will be collected).

[0033] Conclusion: The API in the formulation is distributed in particulate form and has two crystal forms.

[0034] Example 3: Analysis of the distribution patterns of API (mupirocin ointment) and its binding with excipients Step 1: Collect fingerprint peaks for the active pharmaceutical ingredient (API) and excipients separately, and identify the difference peaks to distinguish the API from the excipient in the formulation. This involves taking small amounts of the API (mupirocin) and excipients (polyethylene glycol 3350 and 400) and spreading them on commercially available ordinary glass slides, then pressing them flat with coverslips. Fingerprint peaks are then collected sequentially using a Raman spectrometer. The excitation wavelength is 785 nm, and the spectral acquisition range is 200–3500 cm⁻¹. -1 See Table 3 for characteristic peaks of API and excipients. Figure 13 .

[0035] Table 3

[0036] Step 2: After ultrasonically cleaning the in-situ chip body and coverslip for 5 minutes, use tweezers to place them in an oven to dry, then remove them and place them on the sample preparation table for later use. Use a toothpick to apply the test reagent (mupirocin ointment, brand: Bactroban) into the in-situ chip recess. Use tweezers to gently pick up the coverslip and place it on the in-situ chip body, completely covering the recess. Seal the edges of the coverslip with resin adhesive.

[0037] Step 3: Using a microscope, the area of ​​the test formulation within the in-situ chip is pieced together into a larger area at low magnification (10X), such as... Figure 14 As shown, observe whether there are particles in the sample. Figure 14 The presence of particles indicates that their composition needs to be confirmed.

[0038] Step 4: The particles observed in Step 3 are screened using a polarizing microscope and the regions are then pieced together, such as... Figure 15 As shown. Simultaneously, Raman spectroscopy was used to collect fingerprint peaks of the particles to confirm their composition. Figure 16 It was found that the particles were mainly polyethylene glycol 3350, and no obvious API signal was detected. (During automatic statistics, the particles were simulated as rectangular acquisition centers; when the particle morphology was irregular, the matrix was collected.) Step 5: Based on the above results, no API was found in the particles. Subsequently, Raman spectroscopy imaging was performed on the formulation area (the imaging area should be at least twice the size of the particles within the formulation). Figure 17 The area within the red box in the middle, Figure 18 For the imaging distribution map, Figure 19 The fingerprint peak diagram for the region.

[0039] Conclusion: The API in the formulation is distributed in dissolved form in polyethylene glycol 400.

[0040] This invention also investigates glass slides, as detailed below: 1. Progesterone gel morphology analysis Apply a small amount of the preparation (progesterone gel) to the in-situ chip recess. Gently lift the coverslip with tweezers and place it on the in-situ chip body, completely covering the recess. Seal the edges of the coverslip with resin adhesive. Use a microscope to examine the area of ​​the preparation to be tested within the in-situ chip, such as... Figure 20 , Figure 21 As shown, it is consistent with the true appearance of progesterone.

[0041] Take a small amount of the preparation (progesterone gel) and spread it on a commercially available ordinary glass slide. Then, flatten it with a coverslip. Use a microscope to examine the area of ​​the preparation to be tested on the slide. Figure 22 , Figure 23 As shown, it does not match the true morphology of progesterone.

[0042] It is evident that using commercially available glass slides can alter the particle morphology, ultimately affecting the test results.

[0043] 2. Analysis of the accuracy of the formulation fingerprint peak A small amount of the formulation (ketorolac tromethamine injection) was dropped into the in-situ chip recess. A coverslip was gently placed on the chip body using tweezers, completely covering the recess. The coverslip was then sealed around its edges with resin adhesive. Fingerprint peaks of the formulation were collected using a Raman spectrometer. Figure 24 The blue curved section is shown.

[0044] Take a small amount of the formulation (ketorolac tromethamine injection) and drop it onto a commercially available ordinary glass slide, then flatten it with a coverslip. Use a Raman spectrometer to collect the fingerprint peaks of the above formulation, such as... Figure 24 The red curve indicates this.

[0045] It is evident that commercially available glass slides have poor sealing performance, resulting in the loss of fingerprint peaks and affecting detection accuracy.

[0046] The present invention has been described in detail above, with the aim of enabling those skilled in the art to understand and implement the invention. However, this description should not be construed as limiting the scope of protection of the invention. All equivalent changes or modifications made in accordance with the spirit and essence of the invention should be included within the scope of protection of the invention.

Claims

1. A method for analyzing the distribution pattern of API and its binding mode with excipients in a semi-solid dosage form, wherein the semi-solid dosage form consists of an active pharmaceutical ingredient (API) and excipients, characterized in that... include: (1) Use a Raman spectrometer to obtain the fingerprint peaks of the active pharmaceutical ingredient and excipients and confirm the difference peaks; (2) Load the semi-solid formulation into an in-situ chip, the in-situ chip including an in-situ chip body and a cover glass adapted to the in-situ chip body, the in-situ chip body having an inwardly recessed groove, the loading specifically including delivering the semi-solid formulation into the groove, then covering the in-situ chip body with the cover glass and completely covering the groove, and finally sealing the periphery of the cover glass with the in-situ chip body with sealant; (3) Use a microscope to magnify the sample area to be tested in the in-situ chip by a preset magnification and stitch them together to obtain a large area. Observe whether there are particles or oil droplets in the sample area to be tested. If there are particles, proceed to step (4). If there are no particles or oil droplets, proceed to step (5). If there are no particles but there are oil droplets, proceed to step (6). (4) First, use an optical microscope to screen the observed particles and splice the areas where the screened particles are located. Then, use a Raman spectrometer to collect the fingerprint peaks of the particles. Compare the collected fingerprint peaks with the fingerprint peaks of the active pharmaceutical ingredient and excipients in step (1) to analyze the composition of the particles. If the particles contain the active pharmaceutical ingredient, confirm that the API in the semi-solid preparation is at least partially distributed in particulate form and confirm its crystal form. If the particles do not contain the active pharmaceutical ingredient, confirm that the API in the semi-solid formulation is distributed in a dissolved form, and use a Raman spectrometer to image the sample area where the particles are located to confirm the binding mode of the API and excipients in the semi-solid formulation. (5) Use a Raman spectrometer to image any region of the sample to be tested to confirm the distribution of APIs in the semi-solid formulation and their binding mode with excipients; (6) The oil droplets were imaged using a Raman spectrometer to confirm the distribution of APIs in the semi-solid formulation and their binding with excipients.

2. The analytical method for the distribution pattern of API and its binding mode with excipients in semi-solid dosage forms according to claim 1, characterized in that, The imaging area in steps (4) and (6) is twice or more the area of ​​any observed particle or oil droplet.

3. The analytical method for the distribution pattern of API and its binding mode with excipients in semi-solid dosage forms according to claim 2, characterized in that, The imaging area in steps (4) and (6) is 2 to 5 times the area of ​​any observed particle or oil droplet.

4. The analytical method for the distribution pattern of API and its binding mode with excipients in semi-solid dosage forms according to claim 1, characterized in that, The in-situ chip body also has a fixed area, which is located on the bottom wall of the groove and recessed inward.

5. The analytical method for the distribution pattern of API and its binding mode with excipients in semi-solid dosage forms according to claim 4, characterized in that, The fixed region has multiple regions; and / or, The sum of the depth of the fixed region and the depth of the groove is configured to be 100% to 110% of the maximum diameter of the particles or oil droplets in the semi-solid formulation; and / or, The size of the fixed region is configured to constrain particles or oil droplets in the semi-solid formulation, thereby restricting the movement of the particles or oil droplets within the fixed region.

6. The analytical method for the distribution pattern of API and its binding mode with excipients in semi-solid dosage forms according to claim 1, characterized in that, The cover glass is made of calcium fluoride.

7. The analytical method for the distribution pattern of API and its binding mode with excipients in semi-solid dosage forms according to claim 1, characterized in that, The preset magnification factor in step (3) is 5 to 100 times.

8. The analytical method for the distribution pattern of API and its binding mode with excipients in semi-solid dosage forms according to claim 1, characterized in that, The semi-solid formulation is selected from any one of suspension formulations, gel formulations, cream formulations, and ointment formulations.

9. The analytical method for the distribution pattern of API and its binding mode with excipients in semi-solid dosage forms according to claim 8, characterized in that, The cream formulation includes any one of mometasone furoate cream, imiquimod cream, and mupirocin ointment.

10. The analytical method for the distribution pattern of API and its binding mode with excipients in semi-solid dosage forms according to claim 1, characterized in that, The loading process also includes applying the semi-solid formulation into the groove using a dropper or toothpick.

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