Effect of Active Pharmaceutical Ingredients and...
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dowwolff.com Effect of Plasticizer on Cloud Point of API/HPMC Solutions The cloud point deflection by certain APIs creates a troublesome situation when a coating containing one of these APIs is desired. If an additive could offset the negative effect of the API, this would be of great use in designing formulations. PEG 400 and propylene glycol were selected as targets because they are commonly used plasticizers. They were tested at 1% by mass of the total solution, or 20% of the polymer weight in a 5% hypromellose solution, a common plasticizer level. For both plasticizers, PEG 400 (Figure 6) and propylene glycol (data not shown), the addition of 1% plasticizer at all concentration levels of each API tested did not significantly change the cloud point. These results indicate that the addition of plasticizers will not overcome the cloud point deflection of APIs, but also that they do not cause any additional negative effects relevant to cloud point. Conclusions This study assessed the cloud point deflection behavior of 26 APIs and 6 plasticizers when incorporated into hypromellose formulations. The magnitude of cloud point deflection versus API concentration exhibited a linear relationship in each case studied and the slope of the line fit to each data set was used for comparison. Every ionic API analyzed caused a positive deflection in cloud point and each nonionic additive either exhibited a negative or very minor effect. These observations led to a hypothesis in which the ionic APIs are interacting with the polymer in the same manner as a surfactant: the hydrophobic portion of the amphiphilic molecule is associating with the hydrophobic functional groups of the hypromellose while the charged portion of the molecule is exposed to the aqueous environment, allowing the complex to be soluble. The nonionic molecules will not interact in this manner, but could be taking part in a separate mechanism in which hydrophilic species dehydrate the polymer, resulting in aggregation of the hydrophilic regions and lowering the solubility. The results of this study do not yield a model to determine the magnitude of cloud point deflection, but trends observed do aid in predicting which additives are likely to cause a significant change in this behavior. The plasticizers studied did not significantly affect cloud point of the HPMC solutions except at unusually high plasticizer levels. They did not appear to be of use in mitigating negative effects caused by nonionic APIs. -30 -20 -10 0 10 20 30 0 1 2 3 4 Cloud Point Deflection (°C) API Concentration (%) Acetominaphen, 1% PEG 400 Naproxen Sodium, 1% PEG 400 Theophylline, 1% PEG 400 Caffeine, 1% PEG 400 Acetominaphen, 0% PEG 400 Naproxen Sodium, 0% PEG 400 Theophylline, 0% PEG 400 Caffeine, 0% PEG 400 -100 -50 0 50 100 150 Cloud Point Deflection (°C)/API Concentration (M) Low Viscosity HPMC 2910 Very Low Viscosity HPMC 2906 Amitriptyline HCl Naproxen Sodium Diphenhydramine HCl Triprolidine HCl Metoprolol Tartrate CPM Amoxicillin Phenylephrine HCl Caffeine Atenolol Theophylline Acetaminophen -600 -400 -200 0 200 Cloud Point Deflection (°C)/API Concentration (M) Amitriptyline HCl Naproxen Sodium Diphenhydramine HCl Triprolidine HCl Metoprolol Tartrate CPM Amoxicillin Phenylephrine HCl Caffeine Atenolol Theophylline Acetaminophen Nicotinic Acid HCTZ Captopril Diclofenac Sodium Diltiazem HCl Propanolol HCl Ibuprofen Sodium Timolol Maleate Doxylamine Succinate Ranitidine HCl Hydralazine HCl Isoniazid Metronidazole Metoformin HCl -30 -20 -10 0 10 20 30 0 1 2 3 4 5 Cloud Point Deflection (°C) API Concentration (%) Naproxen Sodium (ionic) Amitriptyline HCl (ionic) Metoprolol Tartrate (ionic) Caffeine (nonionic) Acetaminophen (nonionic) Hydrochlorothiazide (nonionic) Effect of Active Pharmaceutical Ingredients and Plasticizers on the Cloud Point of Hypromellose Formulations Jaime Curtis-Fisk, 1 Paul Sheskey, 2 Chris Tucker 1 1 Formulation Science, Core R&D, 2 Dow-Wolff Cellulosics, The Dow Chemical Company, Midland, MI USA 48674 Effect of Plasticizer on Cloud Point of HPMC Solution Plasticizers are commonly used in tablet coating formulations and therefore their effect on hypromellose cloud point is of interest as well. Plasticizer concentrations of up to 4% of the total solution mass were analyzed. A plasticizer level of 4% is much higher than what would be used in a tablet coating solution, but solutions of this concentration were included to allow direct comparisons between the plasticizer and API results. At a concentration of 1%, all plasticizers deflected the cloud point by less than 2 o C, near the error level of the experiment. The only plasticizer to significantly affect the cloud point was triethyl citrate, at higher concentrations causing a negative deflection of up to 20 o C. Purpose Investigate the effect of active pharmaceutical ingredients (APIs) and plasticizers on the thermal clouding and gelation of solutions of hypromellose excipient polymers. Increasing knowledge in this area can aid in the development of liquid formulations and in under- standing the dissolution properties of solid dosage forms. Materials and Methods The formulations were made from low viscosity (low molecular weight) HPMC 2910 (METHOCEL™ E6 Premium LV Cellulose Ether) and very low viscosity HPMC 2906 (METHOCEL™ VLV Premium Cellulose Ethers) supplied by The Dow Chemical Company, Midland, MI USA. Sample Preparation. Sample preparation was conducted using the high throughput solubility workflow outlined in Figure 1. The software application Library Studio (FreeSlate Inc., Sunnyvale, CA, USA) was used to design the high-throughput solubility experiments and convert the design into a template that could be used by robotic liquid handlers. Sample Analysis. To determine the solubility properties of the formulations, the completed 8 x 12 plate of vials was placed in a custom-built phase identification and characterization apparatus (PICA II). Up to six sample plates can be placed on the deck of this robot, and their temperature controlled using a recirculating bath. Thermal gelation is observed by heating the samples from 20 o C to 80 o C, periodically removing the vials to obtain digital images of the progress of the gelation reaction. Cloud Point Measurements. Cloud point measurements were performed using a 48-sample temperature scanning turbidity (TST) instrument, developed and built at Dow (Figure 2). The instrument described in the previous section collects similar data but each individual vial must be imaged separately for every temperature. The TST instrument is designed to analyze the thermal clouding behavior of many samples in parallel. For this study the cloud point is defined as a 5% decrease in light transmission of the HPMC solution. Results Effect of API on Cloud Point of HPMC Solution All of the APIs analyzed exhibited a linear relationship between drug concentration and cloud point. Representative data sets are shown in Figure 3. Pharmaceutical formulations are generally referred to in terms of percent by mass. When considering the interaction of ingredients with HPMC at the molecular level it would be more useful to compare each molecule in terms of molarity instead of mass. Comparisons of the API structures to the relative slope (change in cloud point per molarity) for each API (Figure 4 and Figure 5) show the clear distinction that all ionic APIs increased the cloud point of the solutions. The nonionic molecules either exhibited a decrease in cloud point or a small increase. Clearly the interaction between the charged (ionic) and neutral (nonionic) APIs is quite different. Figure 3. Effect of selected APIs on cloud point deflection of a 5% HPMC 2910 LV solution. Figure 1. High-throughput workflow for preparing aqueous solutions of polymers and assessing their solubility and phase transition/stability behavior. Figure 4. Effect of API concentration on cloud point deflection of 5% HPMC 2910 LV solution. Figure 5. Effect of API concentration on cloud point deflection of 5% HPMC 2910 LV and HPMC 2906 VLV solutions. Figure 6. Effect of API concentration on cloud point deflection for 5% HPMC 2910 LV solutions without plasticizer and containing 1% PEG 400. ™ ® Trademark of The Dow Chemical Company (“Dow”) or an affiliated company of Dow Form No. 198-02273-1012 Temperature Controller Shaking Light source HT cell assembly CCD camera and lens Temperature Controller Shaking Light source HT cell assembly CCD camera and lens A) B) Figure 2. Schematic and photo of temperature scanning turbidity (TST) instrument setup.
Transcript of Effect of Active Pharmaceutical Ingredients and...
dowwolff.com
Effect of Plasticizer on Cloud Point of API/HPMC Solutions
The cloud point deflection by certain APIs creates a troublesome situation when a coating containing one of these APIs is desired. If an additive could offset the negative effect of the API, this would be of great use in designing formulations.
PEG 400 and propylene glycol were selected as targets because they are commonly used plasticizers.
They were tested at 1% by mass of the total solution, or 20% of the polymer weight in a 5% hypromellose solution, a common plasticizer level.
For both plasticizers, PEG 400 (Figure 6) and propylene glycol (data not shown), the addition of 1% plasticizer at all concentration levels of each API tested did not significantly change the cloud point.
These results indicate that the addition of plasticizers will not overcome the cloud point deflection of APIs, but also that they do not cause any additional negative effects relevant to cloud point.
Conclusions
This study assessed the cloud point deflection behavior of 26 APIs and 6 plasticizers when incorporated into hypromellose formulations. The magnitude of cloud point deflection versus API concentration exhibited a linear
relationship in each case studied and the slope of the line fit to each data set was used for comparison.
Every ionic API analyzed caused a positive deflection in cloud point and each nonionic additive either exhibited a negative or very minor effect. These observations led to a hypothesis in which the ionic APIs are interacting with the polymer in the same manner as a surfactant: the hydrophobic portion of the amphiphilic molecule is associating with the hydrophobic functional groups of the hypromellose while the charged portion of the molecule is exposed to the aqueous environment, allowing the complex to be soluble.
The nonionic molecules will not interact in this manner, but could be taking part in a separate mechanism in which hydrophilic species dehydrate the polymer, resulting in aggregation of the hydrophilic regions and lowering the solubility.
The results of this study do not yield a model to determine the magnitude of cloud point deflection, but trends observed do aid in predicting which additives are likely to cause a significant change in this behavior.
The plasticizers studied did not significantly affect cloud point of the HPMC solutions except at unusually high plasticizer levels. They did not appear to be of use in mitigating negative effects caused by nonionic APIs.
-30
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0 1 2 3 4
Clo
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API Concentration (%)
Acetominaphen, 1% PEG 400
Naproxen Sodium, 1% PEG 400
Theophylline, 1% PEG 400
Caffeine, 1% PEG 400
Acetominaphen, 0% PEG 400
Naproxen Sodium, 0% PEG 400
Theophylline, 0% PEG 400
Caffeine, 0% PEG 400
-100 -50 0 50 100 150Cloud Point Deflection (°C)/API Concentration (M)
Low Viscosity HPMC 2910Very Low Viscosity HPMC 2906
Amitriptyline HCl
Naproxen Sodium
Diphenhydramine HCl
Triprolidine HCl
Metoprolol Tartrate
CPM
Amoxicillin
Phenylephrine HCl
Caffeine
Atenolol
Theophylline
Acetaminophen
-600 -400 -200 0 200Cloud Point Deflection (°C)/API Concentration (M)
Amitriptyline HClNaproxen Sodium
Diphenhydramine HClTriprolidine HCl
Metoprolol Tartrate
CPMAmoxicillin
Phenylephrine HCl
Caffeine
Atenolol
Theophylline
Acetaminophen
Nicotinic Acid
HCTZ
Captopril
Diclofenac SodiumDiltiazem HCl
Propanolol HCl
Ibuprofen SodiumTimolol Maleate
Doxylamine Succinate
Ranitidine HClHydralazine HCl
Isoniazid
MetronidazoleMetoformin HCl
-30
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10
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0 1 2 3 4 5
Clo
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API Concentration (%)
Naproxen Sodium (ionic) Amitriptyline HCl (ionic)Metoprolol Tartrate (ionic) Caffeine (nonionic)Acetaminophen (nonionic) Hydrochlorothiazide (nonionic)
Effect of Active Pharmaceutical Ingredients and Plasticizers on the Cloud Point of Hypromellose Formulations Jaime Curtis-Fisk,1 Paul Sheskey,2 Chris Tucker1
1Formulation Science, Core R&D, 2Dow-Wolff Cellulosics, The Dow Chemical Company, Midland, MI USA 48674
Effect of Plasticizer on Cloud Point of HPMC Solution Plasticizers are commonly used in tablet coating formulations and therefore their
effect on hypromellose cloud point is of interest as well. Plasticizer concentrations of up to 4% of the total solution mass were analyzed. A
plasticizer level of 4% is much higher than what would be used in a tablet coating solution, but solutions of this concentration were included to allow direct comparisons between the plasticizer and API results.
At a concentration of 1%, all plasticizers deflected the cloud point by less than 2oC, near the error level of the experiment. The only plasticizer to significantly affect the cloud point was triethyl citrate, at higher concentrations causing a negative deflection of up to 20oC.
Purpose Investigate the effect of active pharmaceutical ingredients (APIs) and plasticizers on the thermal clouding and gelation of solutions of hypromellose excipient polymers. Increasing knowledge in this area can aid in the development of liquid formulations and in under-standing the dissolution properties of solid dosage forms.
Materials and Methods The formulations were made from low viscosity (low molecular weight) HPMC 2910 (METHOCEL™ E6 Premium LV Cellulose Ether) and very low viscosity HPMC 2906 (METHOCEL™ VLV Premium Cellulose Ethers) supplied by The Dow Chemical Company, Midland, MI USA. Sample Preparation. Sample preparation was conducted using the high throughput solubility workflow outlined in Figure 1. The software application Library Studio (FreeSlate Inc., Sunnyvale, CA, USA) was used to design the high-throughput solubility experiments and convert the design into a template that could be used by robotic liquid handlers. Sample Analysis. To determine the solubility properties of the formulations, the completed 8 x 12 plate of vials was placed in a custom-built phase identification and characterization apparatus (PICA II). Up to six sample plates can be placed on the deck of this robot, and their temperature controlled using a recirculating bath. Thermal gelation is observed by heating the samples from 20oC to 80oC, periodically removing the vials to obtain digital images of the progress of the gelation reaction. Cloud Point Measurements. Cloud point measurements were performed using a 48-sample temperature scanning turbidity (TST) instrument, developed and built at Dow (Figure 2). The instrument described in the previous section collects similar data but each individual vial must be imaged separately for every temperature. The TST instrument is designed to analyze the thermal clouding behavior of many samples in parallel. For this study the cloud point is defined as a 5% decrease in light transmission of the HPMC solution.
Results Effect of API on Cloud Point of HPMC Solution
All of the APIs analyzed exhibited a linear relationship between drug concentration and cloud point. Representative data sets are shown in Figure 3.
Pharmaceutical formulations are generally referred to in terms of percent by mass. When considering the interaction of ingredients with HPMC at the molecular level it would be more useful to compare each molecule in terms of molarity instead of mass.
Comparisons of the API structures to the relative slope (change in cloud point per molarity) for each API (Figure 4 and Figure 5) show the clear distinction that all ionic APIs increased the cloud point of the solutions. The nonionic molecules either exhibited a decrease in cloud point or a small increase. Clearly the interaction between the charged (ionic) and neutral (nonionic) APIs is quite different.
Figure 3. Effect of selected APIs on cloud point deflection of a 5% HPMC 2910 LV solution.
Figure 1. High-throughput workflow for preparing aqueous solutions of polymers and assessing their solubility and phase transition/stability behavior.
Figure 4. Effect of API concentration on cloud point deflection of 5% HPMC 2910 LV solution.
Figure 5. Effect of API concentration on cloud point deflection of 5% HPMC 2910 LV and HPMC 2906 VLV solutions.
Figure 6. Effect of API concentration on cloud point deflection for 5% HPMC 2910 LV solutions without plasticizer and containing 1% PEG 400.
™®Trademark of The Dow Chemical Company (“Dow”) or an affiliated company of Dow Form No. 198-02273-1012
TemperatureController
Shaking
Light sourceHT cell assembly
CCD camera and lens
TemperatureController
Shaking
Light sourceHT cell assembly
CCD camera and lens
A)
B)
Figure 2. Schematic and photo of temperature scanning turbidity (TST) instrument setup.
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