Pretreatment method for detecting clindamycin phosphate gel related substances

Abstract

The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a pretreatment method for detecting clindamycin phosphate gel related substances. Adding the clindamycin phosphate gel into the aluminum potassium sulfate solution, uniformly mixing, and fully reacting the carbomer with the aluminum potassium sulfate solution; after centrifugal separation, supernate is removed, and the obtained supernate is filtered. The pretreatment method provided by the invention not only can separate carbomer from other raw and auxiliary materials and improve the filtering rate so as to improve the detection efficiency, but also can effectively reduce the interference of auxiliary material peaks and improve the detection accuracy.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical analysis, and particularly relates to a pretreatment method for detecting related substances of clindamycin phosphate gel. BACKGROUND

[0002] The information disclosed in this Background section is only for the purpose of increasing an understanding of the general background of the application and does not necessarily constitute an admission or a recognition that the information forms part of the prior art already known to a person of ordinary skill in the art.

[0003] Clindamycin phosphate gel is an external anti-inflammatory drug for antibacterial and anti-inflammatory. The gel matrix of the commercially available clindamycin phosphate gel is mainly carbomer, which has high viscosity and is difficult to be effectively dispersed by conventional solvents. According to the research of the inventors, in the detection of related substances of clindamycin phosphate gel, the presence of carbomer can cause the membrane hole to be blocked during filtration, and the filtration time is as long as 30 minutes or more, and the filtrate is turbid. At the same time, the ultraviolet absorption of carbomer at the detection wavelength can interfere with the identification of impurity peaks, resulting in false positive results. In addition, the existing method of dispersing clindamycin phosphate gel by using a mobile phase as a solvent has the problem that a high-concentration salt solution can easily cause the column pressure to rise, and cannot fundamentally solve the interference of excipients. Therefore, the existing detection of related substances of clindamycin phosphate gel has the problems of low detection efficiency and poor accuracy. SUMMARY

[0004] In order to solve the problems of the prior art, the purpose of the present application is to provide a pretreatment method for detecting related substances of clindamycin phosphate gel, which can not only separate carbomer from other excipients, improve the filtration rate, and thus improve the detection efficiency, but also effectively reduce the interference of excipient peaks and improve the detection accuracy.

[0005] In order to achieve the above-mentioned purpose, the present application provides the following technical scheme: In a first aspect, a pretreatment method for detecting related substances of clindamycin phosphate gel is provided, which comprises the following steps: adding clindamycin phosphate gel into a potassium aluminum sulfate solution and mixing uniformly, and allowing the carbomer to fully react with the potassium aluminum sulfate solution; centrifuging and removing the supernatant, and filtering the obtained supernatant.

[0006] In the present application, an aqueous potassium aluminum sulfate solution is used as a solvent for pretreatment of clindamycin phosphate gel. First, the aqueous potassium aluminum sulfate solution is hydrolyzed to generate aluminum hydroxide colloid, which can neutralize the charge and bridge the carbomer high molecular chain to make it aggregate and precipitate, thereby reducing the viscosity of the solution and improving the filtration rate, and thus improving the detection efficiency. Second, research shows that this solvent can effectively reduce the interference of blank excipient peaks, improve the separation degree of impurity peaks and excipient peaks, and thus improve the detection accuracy.

[0007] In a second aspect, a method for detecting related substances of clindamycin phosphate gel comprises the pretreatment method in the first aspect, and the filtrate obtained by the pretreatment method is detected by high performance liquid chromatography.

[0008] In a third aspect, a kit for detecting related substances of clindamycin phosphate gel comprises a pretreatment solvent or raw materials for preparing the pretreatment solvent; the pretreatment solvent is a potassium aluminum sulfate solution, and the raw materials for preparing the pretreatment solvent are potassium aluminum sulfate and water.

[0009] The present application has the following beneficial effects: 1. The present application uses a potassium aluminum sulfate solution as a solvent for pretreating clindamycin phosphate gel, and solves the problem of filter blockage of the gel sample through a precipitation reaction with carbomer. The filtration time is shortened from 30 minutes in the conventional method to 10 minutes, and the operation efficiency is improved by 60%.

[0010] 2. The present application uses a potassium aluminum sulfate solution as a solvent for pretreating clindamycin phosphate gel, which can effectively reduce the interference of blank excipient peaks and improve the separation degree of impurity peaks and excipient peaks by an average of 3.2 times, thereby significantly improving the detection accuracy.

[0011] 3. The detection method provided by the present application for pretreating clindamycin phosphate gel based on a potassium aluminum sulfate solution has superior detection performance: strong method specificity, a separation degree of each impurity greater than 2.0; high sensitivity, a quantitative limit as low as 0.0011 mg / ml (clindamycin B phosphate); and good durability, the separation degree still meets the requirements when the pH value of the mobile phase is ±0.2 and the flow rate is ±0.2 ml / min.

[0012] 4. The detection method provided by the present application for pretreating clindamycin phosphate gel based on a potassium aluminum sulfate solution has wide applicability. The detection can be completed using an ordinary high performance liquid chromatograph without special instruments, and the detection cost is reduced by 40% compared with the EP method, which is suitable for promotion in different laboratories. BRIEF DESCRIPTION OF DRAWINGS

[0013] The accompanying drawings, which form a part of this application, are included to provide a further understanding of the application and are incorporated in and constitute a part of this application. The embodiments of the present application illustrated in the drawings and their descriptions are used to explain the present application and are not intended to limit the present application.

[0014] Figure 1 FIG. 1 is a comparative chromatogram of a sample solution pretreated with a 0.5% potassium aluminum sulfate solution according to Embodiment 1 of the present application, wherein A is a full spectrum graph, and B is a partial enlarged view of A; Figure 2 FIG. 2 is a comparative chromatogram of a sample solution not pretreated with a 0.5% potassium aluminum sulfate solution according to Embodiment 1 of the present application, wherein A is a full spectrum graph, and B is a partial enlarged view of A; Figure 3 A is a full spectrum, B is a local enlarged view of A, which is a typical chromatogram of the related substance detection of clindamycin phosphate gel in Example 3 of the present application; Figure 4 A is a full spectrum, B is a local enlarged view of A, which is a typical chromatogram of the related substance detection of clindamycin phosphate gel in Example 3 of the present application; DETAILED DESCRIPTION

[0015] It should be noted that the following detailed description is exemplary in nature and is intended to provide further description of the application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0016] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments in accordance with the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and / or "comprising," when used in this specification, specify the presence of stated features, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof.

[0017] The clindamycin phosphate gel described in the present application refers to a clindamycin phosphate gel with a carbomer gel base.

[0018] The potassium aluminum sulfate solution described in the present application refers to a solution prepared by dissolving potassium aluminum sulfate in water.

[0019] In view of the problems of low detection efficiency and poor accuracy in the related substance detection of existing clindamycin phosphate gel, the present application provides a pretreatment method for the related substance detection of clindamycin phosphate gel.

[0020] In a typical embodiment of the present application, a pretreatment method for the related substance detection of clindamycin phosphate gel is provided. The clindamycin phosphate gel is added to a potassium aluminum sulfate solution and mixed uniformly, and the carbomer is allowed to fully react with the potassium aluminum sulfate solution. After centrifugal separation, the supernatant is removed, and the obtained supernatant is filtered.

[0021] In some embodiments, the mass concentration of the potassium aluminum sulfate solution is 0.40-0.60%. The pretreatment effect is better under this condition.

[0022] In some embodiments, the carbomer is vortexed with the potassium aluminum sulfate solution for 30-40 seconds to allow the carbomer to fully react with the potassium aluminum sulfate solution. This condition allows the carbomer to react more fully with the potassium aluminum sulfate solution.

[0023] The turbidity of the supernatant is not higher than 5 NTU. In some embodiments, the centrifugal separation is at a speed of 9000-11000 rpm. Studies show that this speed can effectively precipitate the carbomer particles. Specifically, the centrifugal separation is for 10-15 minutes.

[0024] In another embodiment of the present application, a method for detecting related substances of clindamycin phosphate gel is provided, comprising the pretreatment method described above, and performing high performance liquid chromatography on the filtrate obtained by the pretreatment method.

[0025] In some embodiments, the filtrate obtained by the pretreatment method is diluted with a potassium aluminum sulfate solution, and then subjected to high performance liquid chromatography. The concentration of the potassium aluminum sulfate solution used for dilution is the same as that used in the pretreatment method.

[0026] In some embodiments, in the high performance liquid chromatography, mobile phase A is a mixture of potassium dihydrogen phosphate solution and acetonitrile in a volume ratio of 78-80:22-20, and mobile phase B is a mixture of potassium dihydrogen phosphate solution and acetonitrile in a volume ratio of 39-41:61-59; wherein the pH of the potassium dihydrogen phosphate solution is 5.8-6.2, and the concentration is 0.09-0.11 mol / L. Specifically, the pH of the potassium dihydrogen phosphate solution is adjusted by a potassium hydroxide solution. The mass concentration of the potassium hydroxide solution is preferably 40-50%, and further preferably 44-46%.

[0027] Specifically, in the high performance liquid chromatography, the gradient elution is as shown in the following table:

[0028] In the table, % is the volume percentage.

[0029] In some embodiments, in the high performance liquid chromatography, octadecylsilane-bonded silica gel is used as the filler in the chromatographic column.

[0030] In some embodiments, in the high performance liquid chromatography, the column temperature is 29-31℃.

[0031] In some embodiments, in the high performance liquid chromatography, the flow rate is 0.9-1.1 ml.

[0032] In some embodiments, in the high performance liquid chromatography, the detection wavelength is 208-212 nm.

[0033] In some embodiments, in the high performance liquid chromatography, the injection volume is 19-21 μl.

[0034] The third embodiment of the present application provides a detection kit for clindamycin phosphate gel related substances, comprising a pretreatment solvent or raw materials for preparing the pretreatment solvent; the pretreatment solvent is a potassium aluminum sulfate solution, and the raw materials for preparing the pretreatment solvent are potassium aluminum sulfate and water.

[0035] In some embodiments, the mobile phase solution further comprises mobile phase A and mobile phase B, the mobile phase A is a mixed solution of potassium dihydrogen phosphate solution and acetonitrile in a volume ratio of 78-80:22-20, and the mobile phase B is a mixed solution of potassium dihydrogen phosphate solution and acetonitrile in a volume ratio of 39-41:61-59; wherein the pH of the potassium dihydrogen phosphate solution is 5.8-6.2, and the concentration is 0.09-0.11 mol / L.

[0036] In some embodiments, the blank excipient solution is formed by the blank excipient and the pretreatment solvent.

[0037] In some embodiments, the clindamycin phosphate gel related substance control product further comprises clindamycin B phosphate, clindamycin, impurity F, impurity G, impurity I, impurity J, impurity K, 7-epi-clindamycin phosphate, and clindamycin phosphate.

[0038] The chemical structure of clindamycin B phosphate is:

[0039] The chemical structure of clindamycin is:

[0040] The chemical structure of impurity F is:

[0041] The chemical structure of impurity G is:

[0042] The chemical structure of impurity I is:

[0043] The chemical structure of impurity J is:

[0044] The chemical structure of impurity K is:

[0045] The chemical structure of 7-epi-clindamycin phosphate is:

[0046] The chemical structure of clindamycin phosphate is as follows:

[0047] In order to enable those skilled in the art to more clearly understand the technical solutions of the present application, the technical solutions of the present application will be described in detail below in combination with specific examples.

[0048] Example 1: Sample pretreatment process optimization Solvent screening test: The treatment effects of 0.1 mol / L potassium dihydrogen phosphate solution (pH 6.0)-acetonitrile (79:21), 1 mol / L potassium dihydrogen phosphate solution (pH 6.0)-acetonitrile (79:21) and 0.5% potassium aluminum sulfate solution on samples were compared.

[0049] The results show that after treatment with 0.5% potassium aluminum sulfate solution, the carbomer precipitates completely, the supernatant is clear and transparent after centrifugation, and the filtration speed is increased to 1.2 ml / min, which is 2.5 times higher than that of the conventional salt solution; the number of blank excipient peaks is reduced by 70%, and the peak area recoveries of target impurities such as impurity F and clindamycin B phosphate are all between 95% and 105%, which are superior to other solvents.

[0050] Centrifugation condition optimization: The effects of centrifugation speeds of 5000 rpm, 8000 rpm and 10000 rpm on the precipitation effect were investigated.

[0051] The results show that when centrifuged at 10000 rpm for 10 minutes, the carbomer precipitates have the smallest particle size, the residual amount of carbomer in the supernatant is <0.1%, and the loss rate of target impurities is <0.5%, so the best centrifugation condition is determined.

[0052] The clindamycin phosphate gel was pretreated by using the optimized sample pretreatment process and then subjected to high performance chromatography detection, and the chromatography conditions were as follows: Chromatography conditions: Chromatography column: octadecylsilane bonded silica gel as the filler (XB-C18, 4.6 mm x 150 mm, 5 μm or a chromatography column with equivalent performance); Mobile phase: 0.1 mol / L potassium dihydrogen phosphate solution (pH value adjusted to 6.0 with 45% potassium hydroxide)-acetonitrile (79:21) as mobile phase A, and 0.1 mol / L potassium dihydrogen phosphate solution (pH value adjusted to 6.0 with 45% potassium hydroxide)-acetonitrile (40:60) as mobile phase B, linear gradient elution was performed according to the following table;

[0053] Column temperature: 30°C; Flow rate: 1.0 ml / min; Detection wavelength: 210nm; Injection volume: 20 μl.

[0054] Test results as follows Figure 1 As shown, the test results without sample pretreatment are as follows: Figure 2 As shown, through Figure 1 and Figure 2 The comparison shows that the main peak shape is poor and there is interference from impurities before the sample pretreatment is not used. After the sample pretreatment process optimized in this embodiment is used, the separation and peak shape are good.

[0055] Example 2: Optimization of chromatographic conditions Mobile phase concentration adjustment: Referring to the BP2024 method, the 1 mol / L potassium dihydrogen phosphate solution in mobile phase B was replaced with a 0.1 mol / L potassium dihydrogen phosphate solution to resolve the salting-out issue. The effect of different potassium dihydrogen phosphate concentrations (0.05 mol / L, 0.1 mol / L, and 0.2 mol / L) on the resolution was compared. The results showed that at 0.1 mol / L, the resolution between clindamycin B phosphate and 7-epiclindamycin phosphate was 8.782, meeting the requirement of ≥2.0.

[0056] Gradient elution procedure optimization: The initial gradient (0→10 minutes, 100% mobile phase A) caused the main peak to tail. It was adjusted to 0→20 minutes to maintain 100% mobile phase A. The retention time of the main peak was extended from 11 minutes to 16 minutes, the peak shape symmetry factor was optimized from 1.909 to 1.2±0.1, and the resolution was improved to 9.378.

[0057] Example 3: Methodological Validation method: Preprocessing: Preparation of test solution: Take an appropriate amount of clindamycin phosphate gel (approximately equivalent to 25 mg of clindamycin), place it in a 10 ml volumetric flask, add an appropriate amount of 0.5% potassium aluminum sulfate solution, shake to swell and disperse the gel, vortex for 30 seconds to promote the full reaction of carbomer and solvent, dilute to the mark with solvent, centrifuge at 10,000 rpm for 10 minutes, take the supernatant and filter it through a 0.45 μm nylon membrane, take the filtrate, and obtain the test solution.

[0058] Chromatographic conditions: Chromatographic column: Octadecylsilane-bonded silica gel as the packing material (XB-C18, 4.6mm×150mm, 5μm or equivalent column). Mobile phase: 0.1 mol / L potassium dihydrogen phosphate solution (pH 6.0 adjusted with 45% potassium hydroxide) - acetonitrile (79:21) as mobile phase A, 0.1 mol / L potassium dihydrogen phosphate solution (pH 6.0 adjusted with 45% potassium hydroxide) - acetonitrile (40:60) as mobile phase B, linear gradient elution was carried out according to the following table;

[0059] Column temperature: 30°C; Flow rate: 1.0 ml / min; Detection wavelength: 210 nm; Injection volume: 20 μl.

[0060] Solution preparation: Control solution: 1 ml of the test solution was accurately measured into a 100-ml flask, diluted to the mark with 0.5% aluminum potassium sulfate solution, and shaken well.

[0061] Blank excipient solution: an appropriate amount of blank excipient (about equivalent to 25 mg of clindamycin) was taken into a 10-ml flask, an appropriate amount of 0.5% aluminum potassium sulfate solution was added, shaken and vortexed to dissolve, diluted to the mark with solvent, centrifuged at 10,000 rpm for 10 minutes, the supernatant was filtered (0.45 μm nylon membrane), and the filtrate was taken.

[0062] Sensitivity solution: 1 ml of the control solution was accurately measured into a 10-ml flask, diluted to the mark with 0.5% aluminum potassium sulfate solution, and shaken well.

[0063] System suitability solution: an appropriate amount of clindamycin phosphate system suitability control (containing clindamycin B phosphate, clindamycin, impurities F, G, I, J, K, 7-epi-clindamycin phosphate and clindamycin phosphate) was taken, dissolved and diluted with 0.5% aluminum potassium sulfate solution to prepare a solution containing about 3 mg per 1 ml.

[0064] Determination method: 20 μl of the test solution and the control solution were accurately measured and injected into the liquid chromatograph, and the chromatogram was recorded. The impurity content was calculated according to the main component self-control method.

[0065] Result: In the chromatogram of the test solution, excluding the peaks of the excipients, the peak area of clindamycin B phosphate should not be more than 1.5 times (1.5%) that of the control solution, the peak area of clindamycin should not be more than 2 times (2.0%) that of the control solution, the peak areas of impurities F and 7-epiclindamycin phosphate should not be more than 1.0% that of the control solution, the peak area of each individual impurity should not be more than 0.2% (0.2%) that of the control solution, the total peak area of other impurities should not be more than 4.0% (4.0%) that of the control solution, the total amount of impurities should not exceed 8.0%, and the chromatographic peaks smaller than the main peak area of the sensitivity solution can be ignored (0.1%).

[0066] Results: A typical chromatogram of the test solution is shown in Figure 3 .

[0067] Specificity test: Peak positioning and interference test: The separation degree of each impurity peak from the main peak is greater than 2.0, the blank excipient solution has no interfering peaks at the retention time of the target impurities, and the solvent does not interfere with the determination, as shown in Figure 4 .

[0068] Forced degradation test: Under the conditions of acid, base, oxidation, and high temperature, the separation degree of the main peak from the degradation product peak is greater than 1.5, the material balance is within the range of 90.0% to 110.0%, and the purity of the main peak is greater than 95.0%, indicating that the method can effectively separate the degradation products.

[0069] System suitability test: In the system suitability solution, the separation degree of impurity G and impurity F is 3.724, the theoretical plate number of each impurity peak is greater than 5000, and the tailing factor is less than 1.5, meeting the verification requirements, as shown in Figure 4 .

[0070] Robustness test: When the flow rate changes by ±0.2 ml / min, the retention time RSD of clindamycin B phosphate is 2.1%, and the separation degree RSD is 1.8%; when the pH value of the mobile phase changes by ±0.2, the peak area RSD of impurity F is 3.2%, and the separation degree is greater than 2.0, indicating that the method has good robustness.

[0071] Limit of quantification and limit of detection test: The limit of quantification concentration of each impurity is less than 1 / 10 of the limit concentration, such as the limit of quantification of clindamycin B phosphate is 0.0011 mg / ml (0.04%), and the detection limit is 0.0004 mg / ml (0.015%). The peak area RSD of the limit of quantification solution is ≤5.26% after 6 repeated injections, meeting the detection requirements.

[0072] Accuracy test: The recovery rate of each impurity was between 82.3% and 113.6%, and the RSD was less than or equal to 7.15%. The average recovery rate of clindamycin B phosphate was 103.7%, and the RSD was 2.93%, indicating that the method had high accuracy.

[0073] Precision test: Repeatability test: the single impurity range of 6 samples was less than 0.1%, and the total impurity range was less than 0.2%; intermediate precision test: the single impurity range of different personnel and instrument determination results was less than 0.1%, and the total impurity range was less than 0.2%, indicating that the method had good precision.

[0074] Solution stability test: The RSD of the peak area of the control solution was 1.38% after being placed at room temperature for 96 hours. The impurity determination results of the test sample solution were all less than 0.1% after being placed at room temperature for 72 hours, indicating that the solution had good stability.

[0075] Example 4: sample inspection Clindamycin phosphate gel samples (batch numbers: 2024080141, 2024112841, HE5771) were taken and detected according to the method of Example 3, and the results were as follows:

[0076] The results showed that the impurities in each batch of samples were within the limit range, and the total amount of impurities in the self-prepared preparation was much lower than 8.0%, indicating that the detection results were good, and the practicability of the method was verified.

[0077] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A pretreatment method for detecting related substances of clindamycin phosphate gel, characterized by, The clindamycin phosphate gel is added into the potassium aluminum sulfate solution and mixed uniformly, and the carbomer is fully reacted with the potassium aluminum sulfate solution; after centrifugal separation, the supernatant is removed, and the obtained supernatant is filtered.

2. The pre-treatment method of claim 1, wherein the pre-treatment method is characterized by, The mass concentration of the potassium aluminum sulfate solution is 0.40-0.60%.

3. The pre-treatment method of claim 1, wherein the pre-treatment method is characterized by, The carbomer is vortexed with the potassium aluminum sulfate solution for 30-40 seconds, so that the carbomer is fully reacted with the potassium aluminum sulfate solution.

4. The pre-treatment method of claim 1, wherein the pre-treatment method is characterized by, The centrifugal speed is 9000-11000 rpm.

5. A method for detecting related substances of clindamycin phosphate gel, characterized by, The filtrate obtained by the pretreatment method is subjected to high performance liquid chromatography detection.

6. The detection method as described in claim 5, characterized in that, In the high performance liquid chromatography detection, the mobile phase A is a mixed solution of potassium dihydrogen phosphate solution and acetonitrile in a volume ratio of 78-80:22-20, and the mobile phase B is a mixed solution of potassium dihydrogen phosphate solution and acetonitrile in a volume ratio of 39-41:61-59; wherein the pH of the potassium dihydrogen phosphate solution is 5.8-6.2, and the concentration is 0.09-0.11 mol / L.

7. The method of claim 6, wherein the step of detecting is characterized by In the high performance liquid chromatography detection, the gradient elution is as shown in the following table: In the table, % is the volume percentage.

8. The detection method of claim 5, wherein in the high performance liquid chromatography detection, the chromatographic column uses octadecylsilane-bonded silica gel as the filler; Or, in the high performance liquid chromatography detection, the detection column temperature is 29-31℃; Or, in the high performance liquid chromatography detection, the detection flow rate is 0.9-1.1 ml; Or, in the high performance liquid chromatography detection, the detection wavelength is 208-212 nm; Or, in the high performance liquid chromatography detection, the sample injection volume is 19-21 μl.

9. A test kit for the determination of related substances of clindamycin phosphate gel, characterized in that, The pretreatment solvent or raw material for preparing the pretreatment solvent; the pretreatment solvent is a potassium aluminum sulfate solution, and the raw material for preparing the pretreatment solvent is potassium aluminum sulfate and water.

10. The test kit according to claim 9, wherein the test kit comprises a plurality of the test strips according to claim 1. The mobile phase solution includes mobile phase A and mobile phase B, the mobile phase A is a mixed solution of potassium dihydrogen phosphate solution and acetonitrile in a volume ratio of 78-80:22-20, and the mobile phase B is a mixed solution of potassium dihydrogen phosphate solution and acetonitrile in a volume ratio of 39-41:61-59; wherein the pH of the potassium dihydrogen phosphate solution is 5.8-6.2, and the concentration is 0.09-0.11 mol / L; Or, the blank excipient solution is configured by a blank excipient and a pretreatment solvent; Or, it further includes a clindamycin phosphate gel related substance reference substance, and the reference substance includes clindamycin B phosphate, clindamycin, impurity F, impurity G, impurity I, impurity J, impurity K, 7-epi-clindamycin phosphate, and clindamycin phosphate.

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