Process for the preparation of penicillin v potassium free from protein

Abstract

The application provides a protein removal process for preparing penicillin V potassium, relates to preparation of chemical raw medicine, and particularly relates to the technical field of penicillin V potassium preparation. In the application, the acidification and maturation of the impure protein in the upstream are performed to pre-transform the impure protein into an aggregated state, and a loose filter cake is formed on the membrane surface. During cross-flow filtration, the periodic pulsating flow generated by the high-pressure pump controlled by the control panel cooperates with the energy accumulator connected to the outlet pipeline of the concentrated liquid to form a non-steady shear flow field in the membrane channel, thereby reducing the deposition of the filter cake on the membrane surface.

Description

Technical Field

[0001] This invention relates to the preparation of chemical pharmaceutical raw materials; in particular, it relates to the field of penicillin V potassium preparation technology, specifically a process for preparing penicillin V potassium by removing proteins. Background Technology

[0002] Potassium penicillin V is produced by microbial fermentation. After removing mycelial residue through drum filtration or plate and frame filtration, the resulting filtrate still contains soluble proteins. The presence of these proteins can cause severe emulsification and reduced crystal purity in subsequent extraction processes, and increase the risk of the finished product failing to meet pyrogen standards. Therefore, protein removal is a crucial step in the extraction and purification process of potassium penicillin V.

[0003] Membrane separation technology has been introduced into the field of penicillin fermentation broth protein removal, using membrane tubes to perform cross-flow filtration of the filtrate to retain impurities such as proteins. When these proteins reach the membrane surface in a dissolved state, they form a dense gel layer, leading to a decrease in membrane flux. To maintain flux, it is often necessary to increase membrane rejection precision or cross-flow velocity. Increasing rejection precision further reduces flux, while increasing cross-flow velocity increases energy consumption. Furthermore, existing technologies also include methods to introduce gas to form a gas-liquid two-phase flow to enhance membrane surface cleaning; however, gas injection systems are complex and pose risks of foaming, protein denaturation, and product oxidation. Existing membrane filtration systems largely rely on single transmembrane pressure differential monitoring, which cannot distinguish between reversible fouling and irreversible pore blockage, resulting in poor flushing timing or untimely membrane tube replacement, thus affecting production efficiency.

[0004] Therefore, a process for preparing penicillin V potassium with protein removal is provided. Summary of the Invention

[0005] To address the problems mentioned in the background art, the present invention provides the following technical solution: a method for preparing penicillin V potassium with protein removal, characterized by comprising the following steps:

[0006] S1. Mix the potassium penicillin V filtrate with acid, adjust the pH to the acidic range that causes the impurities to aggregate, and then mature the impurities to change from a dissolved state to an aggregated state to obtain a matured solution.

[0007] S2 feeds the aging solution into the membrane tube for cross-flow filtration. During the filtration process, the speed of the high-pressure pump is periodically changed by controlling the control panel. This works in conjunction with the accumulator connected to the concentrate outlet pipe to generate a periodic pulsating flow in the solution entering the membrane tube, forming an unsteady shear flow field inside the membrane tube.

[0008] S3 acquires the transmembrane pressure difference and membrane permeability of the membrane tube, and extracts the characteristic parameters of the pulsating component in the transmembrane pressure difference corresponding to the frequency of the periodic pulsating flow; based on the changes in the characteristic parameters and membrane permeability, the amplitude and / or frequency of the periodic pulsating flow are adjusted via the control panel; when the characteristic parameters meet the preset conditions, the speed of the high-pressure pump is instantaneously increased via the control panel to form a pulse flow along the membrane surface in the membrane tube, performing forward pulse flushing on the membrane tube; when the membrane permeability drops to a preset threshold, and remains below the preset proportion of the initial membrane permeability after multiple consecutive forward pulse flushes, a prompt to replace the membrane tube is issued via the control panel.

[0009] S4 Collect the permeate from the membrane tube to obtain penicillin V potassium solution after protein removal.

[0010] The present invention has the following beneficial effects:

[0011] 1. This invention pre-converts impurities into aggregates by acidifying and ripening them upstream, forming a loose filter cake on the membrane surface. During cross-flow filtration, a high-pressure pump controlled by a control panel generates a periodic pulsating flow, which works in conjunction with an accumulator connected to the concentrate outlet pipe to create a non-steady-state shear flow field within the membrane channel, reducing filter cake deposition on the membrane surface.

[0012] 2. This invention uses signals from the inlet and outlet pressure gauges and the flow meter via a control panel to calculate the transmembrane pressure difference and membrane permeability, and extracts the characteristic parameters of the pulsating component. The pressure waves generated by the periodic pulsating flow within the membrane channel are damped after a filter cake layer forms on the membrane surface, resulting in amplitude attenuation and phase lag of the pulsating pressure waves. The thicker or denser the filter cake, the more significant the amplitude attenuation and phase lag; therefore, the characteristic parameters of the pulsating component reflect the thickness and structure of the filter cake on the membrane surface. Membrane permeability reflects the membrane tube's ability to allow solvent in the feed solution to pass through. Combining these two parameters allows for the differentiation between reversible membrane fouling and irreversible membrane pore blockage: when the characteristic parameters deteriorate but the membrane permeability can recover after a positive pulse flush, the pulsation is strengthened or a positive pulse flush is triggered; when the membrane permeability continues to decline and multiple positive pulse flushes fail to restore it, it indicates irreversible membrane pore blockage, and the control panel issues a prompt to replace the membrane tube. Forward pulse flushing generates a pulse flow along the membrane surface by controlling the speed of the high-pressure pump to increase instantaneously. This creates a shearing and scouring effect on the membrane surface, removing the filter cake deposited on the membrane. The flushed liquid is discharged from the membrane outlet pipe and returned to the jacket tank, eliminating the need for a flushing pipeline on the permeate side.

[0013] 3. This invention improves the timing of rinsing through a collaborative diagnostic approach, reducing flux decline due to untimely rinsing and product loss due to over-rinsing. Simultaneously, by analyzing membrane permeability trends, it provides a prompt to replace the membrane tubing when irreversible blockage occurs, reducing downtime caused by tubing failure. Even with a membrane molecular weight cutoff increased to 10000 Da, protein removal efficiency remains above 96.5%, and potency recovery remains above 97.2%.

[0014] Of course, any product implementing this invention does not necessarily need to achieve all of the above advantages at the same time. Attached Figure Description

[0015] Figure 1 A schematic diagram of the device for implementing the present invention.

[0016] Figure 2 This is a schematic diagram of the particle size detection of impurities before maturation according to the present invention.

[0017] Figure 3 This is a schematic diagram of particle size detection of aged miscellaneous proteins according to the present invention.

[0018] In the diagram: 1-Jacketed material tank, 2-Cooling water inlet, 3-Drain valve, 4-Feed pipe, 5-Pipeline filter, 6-High-pressure pump inlet, 7-Membrane outlet pipe, 8-Heat dissipation window, 9-Dialysate outlet, 10-Flow meter, 11-Pressure regulating valve, 12-Power switch, 13-Run switch, 14-Control panel, 15-Membrane outlet pressure gauge, 16-Main unit, 17-Accumulator, 18-Concentrate outlet, 19-Pressure relief valve, 20-Membrane inlet pressure gauge, 21-Membrane tubing. Detailed Implementation

[0019] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0020] The technical solution of the present invention will now be described in detail with reference to the accompanying drawings. The data acquisition methods described below are divided into three categories: direct reading, calculation, and detection, which will be noted one by one below. The preset thresholds used in the embodiments are illustrative only; those skilled in the art can set specific values ​​according to the actual membrane tube specifications, feed liquid characteristics, and process requirements.

[0021] Example 1: Equipment Structure

[0022] like Figure 1As shown, the equipment for implementing this process includes a jacketed material tank 1, a main unit 16, a membrane tube 21, and a control panel 14. The jacketed material tank 1 is equipped with a cooling water inlet 2. The main unit 16 houses a high-pressure pump, whose inlet is a high-pressure pump inlet 6. The high-pressure pump inlet 6 is connected to the jacketed material tank 1 via a feed pipe 4, which is sequentially equipped with a pipe filter 5 and a drain valve 3. The membrane tube 21 is fixed to the main unit 16 and has a concentrate outlet 18, a membrane outlet pipe 7, and a dialysate outlet 9. The outlet of the high-pressure pump is connected to the concentrate outlet 18 of the membrane tube 21. Along the liquid flow direction, the concentrate outlet 18 is sequentially equipped with an accumulator 17, a pressure relief valve 19, and an inlet pressure gauge 20. The membrane outlet pipe 7 is equipped with an outlet pressure gauge 15 and a flow meter 10. The main unit 16 also includes a heat dissipation window 8, a pressure regulating valve 11, a power switch 12, a running switch 13, and a control panel 14. The control panel 14 integrates frequency converter control and data processing functions, is electrically connected to the high-pressure pump, and is also connected to the inlet pressure gauge 20, outlet pressure gauge 15, and flow meter 10 respectively.

[0023] Example 2: Signal Processing Logic of the Control Panel

[0024] Calculation of transmembrane pressure differential: The inlet pressure is read directly from the inlet pressure gauge 20, and the outlet pressure is read directly from the outlet pressure gauge 15. The transmembrane pressure differential is the average of the inlet and outlet pressure readings. The permeate side is open to the atmosphere, and its gauge pressure is zero; therefore, the transmembrane pressure differential is this average pressure value.

[0025] Membrane permeability calculation: The concentrate flow rate is directly read from the flow meter 10. The feed flow rate is calculated from the control panel 14 based on the speed and displacement characteristics of the high-pressure pump, according to pump flow calculation methods known in the art.

[0026] The permeate flow rate is calculated using the following formula: Permeate flow rate = Feed flow rate - Concentrate flow rate.

[0027] Membrane permeability is calculated using the following formula: Membrane permeability = Permeate flow rate ÷ (Membrane area × Transmembrane pressure difference). The initial membrane permeability is automatically calibrated and recorded by control panel 14 after each cleaning or when a new membrane tube is put into use.

[0028] Feature parameter extraction: Control panel 14 performs a fast Fourier transform on the transmembrane pressure difference signal to extract the harmonic component with the same frequency as the periodic change in rotational speed, obtaining the amplitude A and phase φ of this harmonic component. During initial operation, control panel 14 automatically records the reference amplitude A0 and reference phase φ0. The units of A and A0 are MPa, and the units of φ and φ0 are degrees (°).

[0029] Preset condition judgment: Control panel 14 calculates the amplitude attenuation ratio and phase offset according to the following formula:

[0030] Amplitude attenuation ratio = (A0 - A) ÷ A0 × 100%

[0031] Phase offset = φ - φ0

[0032] When the amplitude attenuation ratio or phase shift reaches the corresponding preset threshold, it is determined that the preset conditions for triggering forward pulse flushing are met. The rate and absolute value of membrane permeability decrease are also considered in the determination. In this embodiment, the preset thresholds are set as follows:

[0033] Adjust the preset threshold for amplitude: amplitude attenuation ratio is 40%;

[0034] Preset thresholds for triggering positive pulse flushing: amplitude attenuation ratio of 50%, or membrane permeability decreasing to 80% of initial membrane permeability;

[0035] Threshold for membrane permeability recovery after positive pulse flushing: Membrane permeability recovers to more than 90% of the initial membrane permeability;

[0036] The preset threshold for membrane tube replacement prompts is: after multiple consecutive positive pulse flushes, the membrane permeability is still lower than the initial membrane permeability by a preset percentage, which is 70% in this embodiment;

[0037] The preset number of consecutive attempts is 3.

[0038] Operating modes of accumulator and positive pulse flushing:

[0039] During normal filtration, the high-pressure pump pumps the feed solution from the jacketed tank 1 through the feed pipe 4 and the high-pressure pump inlet 6, and then into the membrane tube 21 through the concentrate outlet 18. The high-pressure pump operates at a periodically varying speed, and the output pulsating pressure wave is transmitted along the liquid flow direction. The accumulator 17 is pressurized and depressurized in the concentrate outlet 18 pipe in sync with the pressure pulsation, working in conjunction with the periodic speed changes of the high-pressure pump to form an unsteady shear flow field within the membrane tube 21. Driven by pressure, the permeate flows out from the dialysate outlet 9, and the concentrate is discharged from the membrane outlet pipe 7.

[0040] When control panel 14 determines that a forward pulse flushing is required, it instantaneously increases the speed of the high-pressure pump, thereby increasing the flow rate and velocity of the feed liquid entering the membrane tube 21. This creates a pulse flow along the membrane surface within the membrane tube 21, generating a strong shearing and scouring effect on the membrane surface, flushing away the filter cake deposited there. Accumulator 17 absorbs the pressure surge generated by the instantaneous speed increase of the high-pressure pump during this process. Inlet pressure gauge 20, located downstream of accumulator 17, measures the actual inlet pressure after buffering by accumulator 17. After flushing, control panel 14 controls the high-pressure pump to resume normal periodic operation. The flushed liquid, carrying the detached filter cake, is discharged from outlet pipe 7 and returned to jacketed feed tank 1.

[0041] Example 3: Acidification and Aging Process and Cross-flow Filtration Operation Case

[0042] The penicillin V potassium fermentation filtrate obtained from drum filtration was collected. Initial pH and temperature were directly read using a pH meter and thermometer, respectively; the initial pH was 6.5 and the temperature was 15℃. The concentration of contaminating proteins was measured using the Bradford method after sampling, and the result was 7.8 mg / mL. The initial average particle size of contaminating proteins was measured using dynamic light scattering after sampling, and the result was 12 nm (reference). Figure 2 ).

[0043] S1: Add the filtrate to jacketed tank 1, add the acidic mother liquor from the penicillin V potassium fermentation system, and adjust the pH to 5.0. The pH is read directly from a pH meter. Cooling water is introduced through cooling water inlet 2, and the temperature of the liquid is controlled at 15℃, read directly from a thermometer. The maturation time is 5 minutes to obtain the matured liquid. After maturation, a sample is taken, and the average particle size of the impurity proteins is determined using dynamic light scattering, with a result of 160 nm (reference). Figure 3 This indicates that the mixed proteins have changed from a dissolved state to an aggregated state.

[0044] S2: Turn on power switch 12 and operation switch 13. Set the high-pressure pump speed via control panel 14 to a periodic sinusoidal wave pattern with a frequency of 0.5Hz and an amplitude of 20% of the average speed. The maturation solution enters the high-pressure pump through pipeline filter 5 and high-pressure pump inlet 6, and then enters the membrane tube 21 (with a molecular weight cutoff of 8000 Da) from concentrate outlet 18 for cross-flow filtration. The periodic pulsation of the high-pressure pump, in conjunction with the accumulator 17, creates an unsteady shear flow field within the membrane channel. The operating pressure is regulated by pressure regulating valve 11, and the pressure value is directly read from inlet membrane pressure gauge 20 and outlet membrane pressure gauge 15, controlled at 0.3MPa. Pressure relief valve 19 provides overpressure protection. The equipment operates at a constant flux of 28LMH.

[0045] S3: Control panel 14 collects data from inlet membrane pressure gauge 20, outlet membrane pressure gauge 15, and flow meter 10, calculates transmembrane pressure difference and membrane permeability according to the processing logic described in Example 2, and extracts amplitude A and phase φ. In the initial operation phase, A0 = 0.015 MPa, φ0 = 5°, and the initial membrane permeability value is 42 L / (m²·h·MPa).

[0046] In this embodiment, the preset threshold for adjusting the amplitude is 40% of the amplitude attenuation ratio; the preset threshold for triggering positive pulse flushing is 50% of the amplitude attenuation ratio or the membrane permeability drops to 80% of the initial membrane permeability.

[0047] When running for 45 minutes, A decayed to 0.0087 MPa. The decay ratio was (0.015 - 0.0087) ÷ 0.015 × 100% = 42%, which exceeded the 40% threshold. The control panel 14 automatically increased the amplitude of the speed change from 20% to 30% of the average speed.

[0048] When running for 68 minutes, A continued to decrease to 0.0072 MPa, with a decrease ratio of (0.015 - 0.0072) ÷ 0.015 × 100% = 52%, exceeding the 50% threshold. Control panel 14 triggered a positive pulse flush: the speed of the high-pressure pump was increased instantaneously, forming a pulse flow along the membrane surface in the membrane tube 21 to positively flush the membrane surface for 15 seconds.

[0049] After rinsing, the membrane permeability recovered to 39.5 L / (m²·h·MPa), which is 94% of the initial value (calculated as: 39.5 ÷ 42 × 100% = 94%), and the amplitude A recovered to 0.0142 MPa, close to A0.

[0050] In this embodiment, the membrane permeability recovery threshold after forward pulse flushing is 90% of the initial membrane permeability. The membrane permeability recovery rate after flushing is 94%. If the 90% threshold is exceeded, the equipment continues to operate. During operation, the drain valve 3 is opened every 2 hours. By controlling the opening degree and opening duration of the drain valve 3, a concentrate equivalent to 5% of the feed volume flow rate is discharged to maintain the concentration balance of impurities (i.e., contaminants composed of matured impurities retained by the membrane tube) in the jacket tank 1.

[0051] S4: Collect the permeate flowing out of dialysate outlet 9. After sampling the permeate, the protein removal rate was determined by the Bradford method, and the result was 98.2%; the recovery rate of penicillin V potassium was determined by high performance liquid chromatography, and the result was 98.5%.

[0052] Example 4: Verification of pH and ripening temperature extreme values

[0053] Using the same penicillin V potassium fermentation filtrate and equipment as in Example 3, but changing the pH and maturation temperature conditions in S1, and with the remaining steps the same as in Example 3, the following four groups of experiments were conducted, with each group performed three times, and the results were averaged. Protein removal rate was determined using the Bradford method, potency recovery rate was determined using high performance liquid chromatography, and the average particle size of contaminating proteins was determined using dynamic light scattering.

[0054] Group A: pH 4.8, temperature 15℃, aging for 5 min. After aging, the average particle size of the impurity proteins was 158 nm, the protein removal rate was 98.0%, and the potency recovery rate was 98.3%.

[0055] Group B: pH 5.4, temperature 15℃, aging for 5 min. After aging, the average particle size of the impurity proteins was 155 nm, the protein removal rate was 97.8%, and the potency recovery rate was 98.1%.

[0056] Group C: pH 5.0, temperature 8℃, aging for 5 min. After aging, the average particle size of the impurity proteins was 162 nm, the protein removal rate was 98.3%, and the potency recovery rate was 98.6%.

[0057] Group D: pH 5.0, temperature 25℃, aging for 5 min. After aging, the average particle size of the impurity proteins was 152 nm, the protein removal rate was 97.5%, and the potency recovery rate was 97.8%.

[0058] After running continuously for 8 hours, the membrane flux of all four groups remained above 85% of the initial flux.

[0059] Example 5: Verification of the End Value of the Maturation Residence Time

[0060] Using the same penicillin V potassium fermentation filtrate and equipment as in Example 3, the maturation residence time in S1 was changed, and the remaining steps were the same as in Example 3. The following two sets of experiments were conducted, with each set performed three times, and the average value of the results was taken. Protein removal rate was detected using the Bradford method, potency recovery rate was detected using high-performance liquid chromatography, and the average particle size of impurity proteins was detected using dynamic light scattering.

[0061] Group E: Residence time 3 min, pH 5.0, temperature 15℃. After ripening, the average particle size of the contaminating proteins was 148 nm, the protein removal rate was 97.2%, and the potency recovery rate was 98.0%.

[0062] Group F: residence time 8 min, pH 5.0, temperature 15℃. After ripening, the average particle size of the contaminating proteins was 165 nm, the protein removal rate was 98.5%, and the potency recovery rate was 97.6%.

[0063] Example 6: Verification of the molecular weight cutoff value of the membrane tube

[0064] Using the same penicillin V potassium fermentation filtrate and equipment as in Example 3, membrane tube 21 was replaced with membrane tubes having a molecular weight cutoff of 5000 Da and 10000 Da, respectively. The remaining steps were the same as in Example 3. The following two sets of experiments were conducted, with each set being repeated three times, and the results were averaged. Protein removal rate was detected using the Bradford method, and potency recovery rate was detected using high performance liquid chromatography.

[0065] Group G: Molecular weight cutoff 5000 Da. Protein removal rate 99.1%, titer recovery rate 97.2%, initial membrane flux 22 LMH.

[0066] Group H: Molecular weight cutoff 10000 Da. Protein removal rate 96.5%, titer recovery rate 98.9%, initial membrane flux 35 LMH.

[0067] Example 7: Verification of Pulse Frequency End Values

[0068] Using the same penicillin V potassium fermentation filtrate and equipment as in Example 3, the frequency of the periodic change in the high-pressure pump speed in S2 was changed, and the remaining steps were the same as in Example 3. The following two sets of experiments were conducted, with each set being repeated three times, and the average value of the results was taken.

[0069] Group I: Frequency 0.1Hz. Control panel 14 performs Fast Fourier Transform on the transmembrane pressure difference signal to extract the pulsating component with a frequency of 0.1Hz. After running for 8 hours, the membrane flux remains at 88% of the initial flux.

[0070] Group J: Frequency 1Hz. Control panel 14 performs Fast Fourier Transform on the transmembrane pressure difference signal to extract the pulsating component with a frequency of 1Hz. After running for 8 hours, the membrane flux remains at 91% of the initial flux.

[0071] Example 8: Verification of Terminal Values ​​of Forward Pulse Flushing Parameters

[0072] Using the same penicillin V potassium fermentation filtrate and equipment as in Example 3, when the membrane permeability decreased to 80% of the initial value, one of the two parameters—the rotation speed factor and the flushing duration—was changed, while the other parameter remained unchanged, to verify the independent effect of each parameter on the flushing effect. The experiment was divided into a rotation speed factor experimental group and a flushing duration experimental group, each of which was repeated three times, and the results were averaged.

[0073] Rotation speed multiplier experimental group (rinsing time fixed at 15s):

[0074] Group K1: Rotation speed 1.5 times, rinsing time 15 seconds. After rinsing, the membrane permeability recovered to 88% of the initial value.

[0075] Group K2: Rotation speed 2.0 times, rinsing time 15 seconds. After rinsing, the membrane permeability recovered to 96% of the initial value.

[0076] Rinsing time experimental group (rotation speed fixed at 1.8 times):

[0077] Group K3: Rotation speed 1.8 times, rinsing time 10 seconds. After rinsing, the membrane permeability recovered to 85% of the initial value.

[0078] Group K4: Rotation speed 1.8 times, rinsing time 20 seconds. After rinsing, the membrane permeability recovered to 95% of the initial value.

[0079] The above results indicate that a higher rotation speed ratio leads to a higher membrane permeability recovery rate after rinsing, and a longer rinsing time also leads to a higher membrane permeability recovery rate. In Example 3, a rotation speed ratio of 1.8 and a rinsing time of 15 seconds resulted in a membrane permeability recovery to 94% of its initial value after rinsing. This is similar to the rinsing effects of Group K2 (2.0 times / 15 seconds, 96%) and Group K4 (1.8 times / 20 seconds, 95%), indicating that a rotation speed ratio of 1.8 times and a rinsing time of 15 seconds is a superior parameter combination that balances rinsing effectiveness and energy consumption.

[0080] Example 9: Verification of the membrane tube replacement reminder function

[0081] Using the same penicillin V potassium fermentation filtrate and equipment as in Example 3, an experimental membrane tube 21 with a cumulative operating time of 800 hours was used. The initial membrane permeability was measured to be 18 L / (m²·h·MPa) at the beginning of operation. In this example, the preset threshold for membrane tube replacement was a preset percentage where the membrane permeability remained below the initial membrane permeability after multiple consecutive positive pulse flushes, with the preset percentage being 70%, and the preset number of consecutive flushes being 3. During operation, the membrane permeability continued to decrease, triggering a total of 5 positive pulse flushes. After each flush, the membrane permeability was 17.5, 16.8, 15.9, 14.2, and 11.5 L / (m²·h·MPa), with recovery percentages of 97%, 93%, 88%, 79%, and 64%, respectively (recovery percentage = membrane permeability after flushing ÷ initial membrane permeability × 100%). After the fifth flush, the membrane permeability dropped to 11.5 L / (m²·h·MPa), with a recovery rate of 64%, which is lower than the preset threshold of 70%. Furthermore, the recovery rates (88% and 79%) after the third and fourth flushes had been below 90% for several consecutive times, indicating that irreversible blockage had occurred in the membrane pores. The control panel 14 issued a prompt to replace the membrane tube 21.

[0082] As can be seen from Examples 3 to 9 above, the process of the present invention can be effectively implemented within the range of pH 4.8 to 5.4, maturation temperature 8℃ to 25℃, maturation residence time 3min to 8min, membrane tube molecular weight cutoff 5000Da to 10000Da, pulsation frequency 0.1Hz to 1Hz, and high-pressure pump speed of 1.5 to 2 times the normal speed and rinsing time of 10s to 20s during forward pulse rinsing. The protein removal rate is maintained above 96.5%, the potency recovery rate is maintained above 97.2%, and the control panel 14 can determine the membrane tube life and issue a replacement prompt based on the change in membrane permeability.

Claims

1. A process for preparing penicillin V potassium with protein removal, characterized in that, Includes the following steps: S1. Mix the potassium penicillin V filtrate with acid, adjust the pH to the acidic range that causes the impurities to aggregate, and then mature the impurities to change from a dissolved state to an aggregated state to obtain a matured solution. S2 sends the aging liquid into the membrane tube for cross-flow filtration, and during the filtration process, the speed of the high-pressure pump is periodically changed by the control panel (14), which works in conjunction with the accumulator (17) connected to the pipe of the concentrate outlet (18) to generate periodic pulsating flow in the liquid entering the membrane tube, forming an unsteady shear flow field in the membrane tube. S3 acquires the transmembrane pressure difference and membrane permeability of the membrane tube, and extracts the characteristic parameters of the pulsating component in the transmembrane pressure difference corresponding to the frequency of the periodic pulsating flow; according to the characteristic parameters and the change in membrane permeability, adjusts the amplitude and / or frequency of the periodic pulsating flow through the control panel (14); when the characteristic parameters meet the preset conditions, controls the speed of the high-pressure pump to increase instantaneously through the control panel (14), forming a pulse flow along the membrane surface direction in the membrane tube, and performing positive pulse flushing on the membrane tube; When the membrane permeability drops to a preset threshold and remains below the preset ratio of the initial membrane permeability after multiple consecutive positive pulse flushes, a prompt to replace the membrane tube is issued through the control panel (14). S4 Collect the permeate from the membrane tube to obtain penicillin V potassium clear solution after protein removal.

2. The method according to claim 1, characterized in that, In S3, the transmembrane pressure difference is calculated using the measured values ​​of the inlet and outlet pressure gauges, and the average value of the inlet and outlet pressure gauge readings is taken as the transmembrane pressure difference. The membrane permeability is obtained by dividing the permeate flow rate of the membrane tube during the cross-flow filtration process by the membrane area and the transmembrane pressure difference, wherein the permeate flow rate is determined by subtracting the concentrate flow rate from the feed flow rate, and the concentrate flow rate is measured by a flow meter installed on the outlet pipe.

3. The method according to claim 1 or 2, characterized in that, The characteristic parameter mentioned in S3 is at least one of the amplitude, attenuation rate, or phase difference of the pulsating component of the transmembrane pressure difference.

4. The method according to claim 3, characterized in that, When the attenuation ratio of the amplitude exceeds a preset ratio or the offset of the phase difference exceeds a preset angle, the positive pulse flushing is triggered.

5. The method according to claim 1, characterized in that, The curing process described in S1 is carried out in a jacketed material barrel, which is equipped with a cooling water inlet. The curing temperature is controlled at 8℃ to 25℃ by the cooling water. The curing residence time is 3min to 8min.

6. The method according to claim 1, characterized in that, The acid used in S1 is the acidic mother liquor of the penicillin V potassium fermentation system itself; the molecular weight cutoff of the membrane tubes mentioned in S2 is 5000 Da to 10000 Da.

7. The method according to claim 1, characterized in that, The liquid after the positive pulse rinsing described in S3 is returned to the container used for aging; a portion of the concentrate is periodically discharged to maintain the concentration balance of contaminants composed of filtered proteins.

8. The method according to claim 1, characterized in that, The acidic range described in S1 is pH 4.8 to 5.4.

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