:Q . .19 a... e n. u‘ .a v 0..., .. .._....,m.... ... “aw... mfll‘ x- 33.. v a. .wnvai... .. J. r w mm ..$ .mapsw aw. .‘I. a; .‘n y .. . .r , r. 4 .1 . 9. ...1..r.:..\ z. ‘ {t . .w . 0 WW... ism. .. 5%... $3. ., Lt. . > . _ J L Q L; a 1 nr v 4. 3. ....,. . a ......s., A1 £511.... 9:51 5| 2 5.31.3.3 .. iii... xv“)... a1 .... s . 7... «c" at. .4? 3...: . i. . a. «W. 9., :I ~ ~ 9...)“ a .2... 2.... E. "WW #an V 1 u v A r .2. .. . u.-. Hfiuafifit w.» .. 4. $3. .r I. ~‘~£ ‘D‘ . 5.. Iu‘ i.- 1 x n... .(5\;.. . J . :2... I... \C THESlS l ZCDl LIBRARY Michigan State Unlverslty This is to certify that the thesis entitled DISSOLUTION SHELF LIFE OF PREDNISONE THERAPEUTIC DOSAGE FORM TABLET presented by Matthew S. Thomas has been accepted towards fulfillment of the requirements for M. S. degree in Packaging Major professor 7 , Dateflgwi 1:47 iAJZUVO 0-7639 MS U is an Affirmative Action/Equal Opportunity Institution PLACE IN RETURN BOX to remove this checkout from your record. TO AVOID FINES return on or before date due. MAY BE RECALLED with earlier due date if requested. DATE DUE DATE DUE DATE DUE woo mm.“ DISSOLUTION SHELF LIFE OF PREDNISONE THERAPEUTIC DOSAGE FORM TABLET by Matthew S. Thomas A Thesis Submitted to Michigan State University In partial fulfillment of the requirements For the degree of MASTER OF SCIENCE School of Packaging 2000 ba leg Abstract DISSOLUTION SHELF LIFE OF PREDNISONE THERAPEUTIC DOSAGE FORM TABLET by Matthew S. Thomas Uncoated 5 mg Prednisone tablets were stored (open dish) in humidity buckets, which included nominal relative humidities (RH) of 12%, 33%, 50%, 65%, 75%, 80% and 90% at three ICH temperatures (250, SOC and 400). Moisture sorption isotherms, initial and critical moisture contents were determined for the product and used in a dissolution shelf life model. Critical moisture content data was generated using a dissolution procedure according to United States Pharmacopoeia (USP) section <711>. Prednisone tablets were stored at conditions mentioned above and dissolution testing was performed in triplicate at each storage condition every three days for approximately two months. Dissolution failures were identified at storage conditions corresponding to RH of 75% and higher for each temperature. The dissolution shelf life model was used to suggest packaging materials, which minimize material costs while providing sufficient protection over a desired shelf life. This study shows that PVC blister materials (low moisture barrier) may not provide enough protection from moisture. So, a higher moisture barrier material, such as 0.6 mil Aclar (more expensive than PVC), may be required. Acknowledgments First of all, my love and appreciation goes out to my family for all of their support throughout the years. Thanks to Mom and Dad for always being there, no matter what the issue. Thanks to my brothers and sisters for being such a big part of my life. Thanks to my wife for being so supportive and patient through the years. I could not have done any of this without you. I would also like to thank my colleagues and the faculty at the School of Packaging for making my second college adventure so memorable. It is this group of people who truly makes the School of Packaging a special place. Special thanks to my committee members; Dr. Hugh Lockhart, Dr. Susan Selke and Dr. Dennis Gilliland. My Acknowledgment would not be complete without sending an added thank you to Dr. Lockhart for his dedication to his profession. Thank you for your guidance and support. I appreciate everything you have done for me. iii List of Tables List of Figures List of Calculations Chapter 1 Chapter 2 Chapter 3 3.1 3.2 3.3 3.4 3.5 Chapter 4 4.1 4.2 4.3 4.4 4.5 Chapter 5 Chapter 6 Appendix A References Table of Contents Introduction Literature Review Materials and Methods Standardizing the Dissolution Procedure Moisture Sorption lsotherms Initial Moisture Content Dissolution Testing Shelf Life Calculations Data and Results Standardizing the Dissolution Procedure Moisture Sorption lsotherms Initial Moisture Content Dissolution Testing Statistical Analysis Conclusions Recommendations for Future Work Dissolution Values (Raw Data) iv 1 3 1 3 15 17 1 9 21 23 23 26 33 36 39 47 48 66 Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 List of Tables Dissolution Calibration Data USP Calibrator Tablet Dissolution Results Salt Solution RH at Three Temperatures Bucket RH Readings for lsotherms Moisture Gain for Prednisone Tablets at 250 Moisture Gain for Prednisone Tablets at 300 Moisture Gain for Prednisone Tablets at 400 Moisture Sorption lsotherm Data Initial Moisture Content of Prednisone 5 mg Tablets Absorbances of Dissolution Profile % Dissolution of Dissolution Profile Summary of Dissolution Data (Averages) Summary of Dissolution Data (Standard Deviations) Summary of Calculated Permeance Values 25C Raw Dissolution Data and Statistics (Day3) 250 Raw Dissolution Data and Statistics (Day6) 250 Raw Dissolution Data and Statistics (Day9) 250 Raw Dissolution Data and Statistics (Day12) 25C Raw Dissolution Data and Statistics (Day15) 25C Raw Dissolution Data and Statistics (Day18) 250 Raw Dissolution Data and Statistics (Day21) 250 Raw Dissolution Data and Statistics (Day24) 23 25 26 27 28 28 29 31 33 34 35 49 49 50 50 51 51 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 250 Raw Dissolution Data and Statistics (Day37) 250 Raw Dissolution Data and Statistics (Day44) 250 Raw Dissolution Data and Statistics (Day51) 250 Raw Dissolution Data and Statistics (Day58) 3OC Raw Dissolution Data and Statistics (Day3) 3OC Raw Dissolution Data and Statistics (Day6) 3OC Raw Dissolution Data and Statistics (Day9) 30C Raw Dissolution Data and Statistics (Day12) 3OC Raw Dissolution Data and Statistics (Day15) 3OC Raw Dissolution Data and Statistics (Day18) 300 Raw Dissolution Data and Statistics (Day21) 300 Raw Dissolution Data and Statistics (Day27) 30C Raw Dissolution Data and Statistics (Day33) 300 Raw Dissolution Data and Statistics (Day40) 3OC Raw Dissolution Data and Statistics (Day47) 3OC Raw Dissolution Data and Statistics (Day54) 4OC Raw Dissolution Data and Statistics (Day3) 40C Raw Dissolution Data and Statistics (Day6) 40C Raw Dissolution Data and Statistics (Day9) 4OC Raw Dissolution Data and Statistics (Day12) 4OC Raw Dissolution Data and Statistics (Day15) 40C Raw Dissolution Data and Statistics (Day18) 40C Raw Dissolution Data and Statistics (Day21) vi 52 52 53 53 54 54 55 55 56 56 57 57 58 58 59 59 6O 6O 61 61 62 62 63 Table 46 Table 47 Table 48 Table 49 Table 50 400 Raw Dissolution Data and Statistics (Day27) 40C Raw Dissolution Data and Statistics (Day33) 4OC Raw Dissolution Data and Statistics (Day40) 4OC Raw Dissolution Data and Statistics (Day47) 4OC Raw Dissolution Data and Statistics (Day54) vii 63 64 64 65 65 Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 List of Figures Dissolution process of solid dosage forms Dissolution rates for various dosage forms USP dissolution method (paddle) Moisture sorption isotherm (example) Dissolution Calibration Curve (1/5/99) Dissolution Calibration Curve (1/6/99) Dissolution Calibration Curve (1/10/99) Moisture Gain for Prednisone Tablets at 250 Moisture Gain for Prednisone Tablets at 300 Moisture Gain for Prednisone Tablets at 400 Moisture Sorption lsotherms Linear Regression of Moisture Sorption Isotherm Prednisone Tablet Dissolution Profile viii 11 24 24 25 29 30 30 31 32 35 Calculation 1 Calculation 2 Calculation 3 Calculation 4 Calculation 5 Calculation 6 List of Calculations Equilibrium Moisture Content Water Activity Initial Moisture Content “dry basis” Initial Moisture Content “wet basis” Absorbance Units from Dissolution Values Shelf Life Equation 16 16 18 18 2O 22 0. TE Introduction Stability testing is required by federal Food and Drug Administration (FDA) regulations. It is taken as a laboratory verification that the drug in its package will continue to meet USP monograph requirements during its expiration dating period (shelf life). The pharmaceutical industry relies on efficient and timely drug development plans, which are often described as “speed to market”. The objective is to get the drug product to market as quickly as possible. The primary responsibility of each participating group in a drug development plan is not to delay the drug development timeline. Every day wasted in the timeline can mean the loss of millions of dollars. Package development groups rely on experience to dictate which packaging materials will be used for product stability testing. Stability testing can be very expensive, so the number of package alternatives should be limited and chosen very carefully. For example, three blister materials may be used to package a product for initial stability testing. Usually these three blisters will incorporate high, medium and low barriers to moisture. If the high barrier material does not protect the product adequately, the stability process must start over. This is the worst case scenario, and should be avoided at all costs. A low barrier material offers the opportunity to save money if the product passes stability requirements. Therefore, such a barrier should be included in stability testing. Prior to putting a package scenario together for a product entering initial stability, any package/product information a packaging engineer can find will be useful. Upon final product formulation, characterization testing of the drug product is performed to provide sensitivity information about that product. These tests take the form of open dish studies at designated ICH (International Conference on Harmonisation) temperatures and relative humidities (RH). If a product formulation is extremely sensitive to moisture or light, for example, the package selections for stability will take this into account. Dissolution shelf life (DSL) can be used for moisture sensitive products to provide additional information before package materials are chosen for stability testing. Since moisture is often the major concern for product sensitivity, the DSL model can prove to be very powerful. The study objectives listed below highlight key areas of this project. 1. Standardize the dissolution testing procedure for recording dissolution data. USP standards were used to develop a calibration curve, which determined the percent dissolution values from absorbance units (AU). These AU were the direct readings from an ultra violet/visible spectrophotometer (UV-Vis). USP dissolution calibrator tablets were used to calibrate the performance of the dissolution apparatus. ("I 2. Determine the initial moisture content of the Prednisone tablets using a Karl Fisher autotitration method. 3. Develop moisture sorption isotherms using a gravimetric method for product stored in open dish at various ICH RH and temperatures. 4. Perform dissolution testing of the product being stored at various ICH temperatures and RH. Determine the critical moisture content of the product from respective dissolution failures, which were used in the shelf life model. The critical moisture content is defined as the moisture content at which the product fails dissolution, or at which there is a significant change in dissolution behavior. 5. Use the critical moisture content in the shelf life model to determine package selection options for stability testing of the drug product. Pharmaceutical companies will conduct many analytical tests during the product characterization phase. These tests can be expensive and time consuming, but they provide essential testing data. Since chemical testing resources were limited at the School of Packaging, one test method (dissolution) was chosen to indicate critical conditions. Dissolution is a physical test based on physical properties. The following quotes verify that dissolution testing is an excellent choice, especially for a moisture sensitive pharmaceutical product. “Dissolution analysis of pharmaceutical solid dosage forms has emerged as the single most important test that, when carried out appropriately, will ensure the quality of the product” (Banaker, 1992). “The importance of dissolution rate on clinical performance of drugs and drug delivery systems has long been recognized. It is the overwhelmingly important property of dosage forms that contributes to the rate and extent of drug availability to the body and, as such, is deserving of the effort that has been put forth to develop dissolution systems that provide fundamental information on the dissolution process of many drugs and chemicals as well as meaningful in vitro dissolution system models that can be correlated with some index of in vivo performance” (Banaker, 1992). “Dissolution testing, of course, is a regular quality control procedure in good manufacturing practice. Whether or not its numbers have been correlated with biological effectiveness, the standard dissolution test is a simple and inexpensive indicator of a product’s physical consistency” (Hanson,1991). This thesis is the sixth in a series of theses reporting the development at the School of Packaging of a method for calculating the moisture barrier requirements for drug products. The two previous theses (Adams, Yoon) are listed in the bibliography. The work done involved method development and application of the method to hard gelatin capsules, coated tablets and two variations of uncoated tablets. Literature Review Many sources have indicated that dissolution is one of the most important tests to verify the efficacy of pharmaceutical products. In fact, over 100 years ago, scientists recognized dissolution as an important prerequisite for drug absorption. Other theses (Adams, Yoon) published at the School of Packaging, based on shelf life modeling, have detailed literature reviews, which highlight the history and importance of dissolution in measuring drug product efficacy. Many studies have correlated drug bioavailability (in-vivo) and drug dissolution (in-vitro). The following schematic illustrates the dissolution process of solid dosage forms (Banakar, 1992). Disintegration Deaggregation b % Tablets or Capsules Dissolution Granules or Aggregates uottnjossgq Drug in Solution (in-vitro or in-vivo) (OAIA-UI) uondJosqv Drug in Blood and Other Fluids Fine Particles Dissolution Figure 1. Dissolution process of solid dosage forms In Figure 1, the rate of drug dissolution can be the rate-limiting step before the drug appears in the blood. This establishes the important link between dissolution and bioavailability. Various dosage forms can have different dissolution rates, which correspond to different bioavailabilities. Figure 2 shows the order of dissolution rates and thus absorption rates for various dosage forms (Banakar, 1992). Fastest Solutions ‘ fl Suspensions (Absorption) Capsules Tablets Slowest Coated Tablets Figure 2. Dissolution rates for various dosage forms Looking back on the long history of dissolution, an important milestone was the development of the USP paddle method in 1978. This is the method used in this study for dissolution testing. This method contains specific requirements for the positioning of the paddles, shaft rotation, medium temperature, etc. Figure 3 illustrates the forced-convection nonsink dissolution testing method of the USP paddle apparatus (Banakar, 1992). Speed (rpm) Shaft Centering (or tilt) Eccentricity Sampling Point Flask Paddle Paddle Position Stainless/Glass Helix Figure 3. USP dissolution method (paddle) suc dis: diffs impc Sectic Which be fer drug‘ rr iaCiOrs é 1' FaClo When a dissolution test is initiated, especially when a new dissolution test is being developed, it is important to recognize all the variables. In the case of this study, specific protocols are followed, such as the procedure developed by the UpJohn Company for Prednisone 5 mg therapeutic tablets. Following a specific procedure will keep dissolution variables to a minimum. “The dissolution-rate data can be meaningful only if the results of successive tests on the same dosage form are consistent within reason. The dissolution test should yield reproducible results even when it is performed in different laboratories or with different personnel” (Banakar, 1992). Looking at the specific parameters involved in dissolution testing, it is very important to minimize the variables within the testing protocol. For example, the preparation of the dissolution medium is a critical step. The USP dissolution section <711> specifically notes, “Dissolved gases can cause bubbles to form, which may change the results of the test. In such cases, dissolved gases should be removed prior to testing.” (USP 23, 1995) When analytical development creates a dissolution procedure for a new drug, many variables are taken into account. Banaker (1992) wrote “The various factors affecting the dissolution rate of a drug from a dosage form fall in six main classes: 1. Factors related to the physicochemical properties of the drug lnl UH wh 2. Factors related to drug product formulation 3. Factors related to dosage form 4. Factors related to dissolution testing device 5. Factors related to dissolution test parameters 6. Miscellaneous factors It must be stated at the outset that this classification is oversimplified for the purpose of understanding their influence on the dissolution process”. The factors listed above, when related to dosage form, can significantly influence dissolution. Depending on the form of the product (coated tablet, uncoated tablet, gelatin capsule), several intermediate steps will be involved, which influence the dissolution process. “The process of dissolution of an active ingredient from solid pharmaceutical dosage forms involves several intermediate physicochemical steps such as wetting, swelling, capillarity, solubility, and diffusion” (Banakar, 1992). For example, wetting is one of the first steps in the dissolution process, in which the outside surface of the product is initially penetrated by the liquid dissolution medium. Development chemists must understand complex variables such as this when new formulations are developed. Minor changes within the formulation can create significant changes in dissolution, which indicates potential problems with bioavailability. The dissolution procedures used in this research were developed with reference to the Dissolution general chapter <711> (USP 23, 1995). As stated earlier, the USP paddle method (Figure 3, Page 7) is the preferred dissolution setup for this product. The assembly is similar to the USP basket method except for a blade, which replaces a basket. To verify that the system is working correctly, a suitability test can be performed using USP Dissolution Calibrator Tablets. These tablets will deliver a specific amount of active ingredient (Prednisone) if the apparatus is functioning correctly. This dissolution chapter (USP<711>) continues to discuss parameters within the test, such as dissolution medium and time. The official monograph for Prednisone tablets can be referenced within the USP for specific dissolution information. A pharmaceutical testing laboratory would implement an in-house procedure, which includes these testing parameters and references the USPS official monograph. Taborsky used dissolution testing to show that Prednisone is a moisture sensitive product. “This study demonstrates a direct correlation between an important performance feature of the pharmaceutical product and the moisture barrier of its packaging” (Taborsky-Urdinola, 1981 ). Taking this study one step further, the dissolution tests can determine a critical storage condition, while moisture isotherms and initial moisture content data can be used to generate shelf life information. Shelf life programs can be utilized to take a product’s moisture sensitivity into account, and determine the proper amount of protection needed to package a pharmaceutical product for a defined shelf life. 10 The shelf life program used in this study was developed at the School of Packaging by Seung-Yil Yoon (Yoon, 2000). The program uses product moisture contents and isotherms and package permeability and dimensional information to determine a shelf life for a specific package selection. The program can also be used to determine the type of package needed for a desired shelf life. For example, the desired shelf life can be entered into the program along with the product information. The program will then calculate the required package permeance to create a given shelf life for a specific product. At this point, the desired package can be selected based on the permeance alone. The program calculates shelf life by either a linear method or the G.A.B. method. Both methods use mathematical expressions to represent a product’s moisture isotherm. The linear method simply uses a linear model, while the G.A.B. model uses a complex non-linear regression. For example, Figure 4 shows a typical moisture isotherm for a dry pharmaceutical product (Adams, 1 998). 12.0 10.0 EMC 8.0 31"“ 6.0 4.0 2.0 - 0.0 0 10 20 30 40 50 60 7O 80 90 100 RH% Figure 4. Moisture sorption isotherm (example) 11 A linear model does not represent the entire curve. However, if the portion of the isotherm, which represents all of the testing conditions, is linear, then that linear equation can be used in the shelf life calculations. 12 PL dis SDE rela Pre (Der MEIhc medlul Predni: the disg ”st as 01330ij determln Chapter 3: Materials and Methods 3.1 Standardizing the Dissolution Procedure Purpose The dissolution procedure must be calibrated to validate the generated dissolution data. Dissolution samples were analyzed by a UV-visible spectrophotometer, which generates absorbance units (AU). These AU are relative numbers, which correspond to specific dissolution values. USP Prednisone standards were used to correlate AU to specific dissolution values (percent dissolution). Materials > VanKel VK6010 Dissolution Apparatus (paddle) > USP Prednisone Reference Standard > UV-Vis Spectrophotometer (Perkin-Elmer, Lambda 20) > USP Calibrator Tablets Methods A specific amount of reference standard was added to the dissolution medium to represent dissolution percentages of 100%, 75%, 50% and 25% for Prednisone tablets. The corresponding absorbance values were plotted versus the dissolution percentages. The resulting linear regression of these points was used as the calibration curve. USP calibrator tablets were then tested in the dissolution apparatus. The dissolution percentage for these tablets was determined by using the calibration curve. Standardization of the dissolution 13 if apparatus was verified by comparing the calibrator tablet’s experimental dissolution percentage to the actual dissolution percentage, which was listed on the Calibrator tablet’s label. 14 Me 001 MM 26" COr the the "is: 3.2 Moisture Sorption isotherms Purpose Determine moisture sorption isotherms of the 5 mg Prednisone tablets at three ICH temperatures (25C, 30C, and 400) by gravimetric methods. Materials > Temperature Chambers for 25C, 300 and 400 > Five-Gallon Plastic Buckets (RH Buckets) > Product Racks and Recrystallization Dishes > “Hygrodynamics” RH Monitoring Equipment > Saturated Salt Solutions (Table 3, Page 26) > 5 mg Prednisone Tablets > Mettler Analytical Balance (+/- 0.05 mg) Methods Each temperature chamber contained seven RH buckets corresponding to nominal RH of 12%, 33%, 50%, 65%, 75%, 80% and 90%. The RH of each bucket was achieved by preparing the appropriate salt solution (Table 3, Page 26) in a Pyrex recrystallization dish. After this dish was placed in the corresponding bucket, the bucket was sealed and allowed to equilibrate before the RH was monitored and product was placed inside. Each bucket contained a product rack, which was placed over the top of the recrystallization dish. This rack allowed an open dish of product to safely rest inside the bucket while being exposed to the RH within the bucket. Each bucket 15 contained 15 Prednisone tablets, which were carefully placed in an aluminum weighing dish (open dish). As the RH buckets equilibrated over a period of at least 24 hours, the RH inside each bucket was measured and recorded (Table 4, Page 27) at various intervals during the test procedure. Once the desired RH was measured for each bucket, fifteen Prednisone tablets were placed in aluminum weighing dishes for each bucket. The weight of the weighing dishes was initially recorded along with the weight of the dish containing fifteen tablets. After approximately two days, all of these dishes (with tablets) were weighed. To verify that the tablets reached an equilibrium moisture content (EMC), periodic weighings continued (Tables 5, 6 and 7; Pages 28, 28 and 29). To construct an isotherm for the Prednisone tablets, the tablet EMC (g*Water/1009 Dry Product) for each temperature was plotted versus the corresponding RH (Figure 11, Page 31). Calculations Equilibrium Moisture Content (EMC) = [(Pf(1+IMC)/Pi)-1]*100 ( 1) Pf = Weight of dry product Pi = Initial weight of product IMC = Initial Moisture Content (g*Water/1009 Dry Product) Water Activity (Aw) = %RH / 100 (2) %RH = Percent Relative Humidity 16 Ml Co On Wet 9.P prOpi theOrl were! 3.3 Initial Moisture Content Purpose The initial moisture content (IMC) data represents the average amount of moisture contained in a five mg Prednisone tablet, when the tablets original container was first opened. The IMC was used in the computer shelf life model. Materials > Brinkmann Karl Fisher Autotitrator > Hydranal Composite 5 Titrant > Deionized Water > HPLC Grade Methanol > Mettler Analytical Balance (+/- 0.05 mg) > Prednisone 5 mg Tablets Methods Prednisone 5 mg tablets were received from the Pharmacia and UpJohn Company in high density polyethylene bottles (approximately 170mLs) containing 1000 tablets. Five tablets were taken out of a new bottle and tested individually on the Brinkmann autotitrator. The autotitrator was set up to calculate MC on a wet weight basis. This MC was converted to a MC on a dry weight basis (Table 9, Page 33). A standardization check was performed to ensure the autotitrator was properly calibrated. Injecting a specific amount of water into the titrator should theoretically yield a value of 100%. Results in triplicate between 98% and 102% were required to confirm the unit was calibrated properly. l7 Calculations Initial Moisture Content (IMC) = [(Wi - Wf) / Wt]*100 “dry basis” (3) IMC = Initial Moisture Content Wi = Weight of product containing initial moisture Wf = Weight of dry product Initial Moisture Content (IMC) = [(Wi - Wf) / Wi]*100 “wet basis” (4) IMC = Initial Moisture Content Wi = Weight of product containing initial moisture Wf = Weight of dry product 18 -\ II: N. Mel Corr plac. Fred RH a di380. tested 3.4 Dissolution Testing Purpose Dissolution testing data was used to identify critical conditions (temperature and RH) and corresponding critical moisture contents, which represented the Prednisone tablets failing, or beginning to fail, USP dissolution limits. Materials > Temperature Chambers for 250, 300 and 400 > Five-Gallon Plastic Buckets (RH Buckets) > Product Racks and Recrystallization Dishes > “Hygrodynamics” RH Monitoring Equipment > Saturated Salt Solutions (Table 3, Page 26) > 5 mg Prednisone Tablets > VanKel VK6010 Dissolution Apparatus (paddle) > UVNis Spectrophotometer (Perkin Elmer, Lambda 20) Methods Five-gallon buckets containing equilibrated saturated-salt solutions, corresponding to specific RH (12%, 33%, 50%, 65%, 75%, 80%, 90%), were placed in three separate chambers set to ICH temperatures (250, 300, 400). Prednisone tablets were placed in these buckets corresponding to the specific RH and temperatures mentioned above. These tablets were tested for dissolution every three days for nearly two months. In addition, tablets were tested at time zero to establish a dissolution profile. For the dissolution profile, 19 ter the we Ca Ab: Abs 9: E dissolution data was generated at 10, 20, 30, 40, 50 and 60 minutes. To determine critical conditions for the Prednisone tablets at the various temperatures and RH, dissolution data was generated at 30 minutes according to the USP dissolution monograph. Per the monograph, less than 80% dissolution was determined to be a failure. Calculations Absorbance (A U) = 0.4576 * (% Dissolution) - 0.0025 (Figure 7) (5) Absorbance (AU) = absorbance units (UVNis) from dissolution samples % Dissolution = percentage of active ingredient in dissolution medium 20 3.! PL me me prc Me Me ge: mc a C this sug m0 Val: be Sin. mat by ll 3.5 Shelf Life Determination Purpose The shelf life computer model recommends the use of specific packaging materials for the Prednisone tablets being studied. The goal is to minimize material costs by choosing the least expensive packaging materials, which provide sufficient protection from moisture over a desired shelf life. Materials > School of Packaging Shelf Life Computer Model (Windows based program for IBM Compatible Computers) Methods The shelf life computer model performs shelf life calculations using data generated for a specific moisture sensitive product. For this study, the initial moisture content, moisture sorption isotherm data, critical moisture contents, and a desired shelf life value, are entered into the shelf life computer model. From this data, a permeance value is generated. This permeance value is used to suggest a packaging material, which minimizes costs and provides sufficient moisture protection for a desired shelf life. For example, looking at permeance values for various blister materials, a specific material’s permeance value must be lower than the permeance value specified by the shelf life computer model. Since higher moisture barrier materials tend to be more expensive, choosing a material which has a permeance value closest to the permeance value generated by the shelf life computer program will minimize material costs. 21 Calculations The calculation for the linear model is: t: (I " W *B/A " P *pS) “In [(FIH. — HH;)/(RH9 - RHC)] (6) t = Desired Product Shelf Life I = Material Thickness W = Product Weight B = Slope of “EMC (g*Water/1009 Dry Product) versus Aw" Graph (Unitless) A = Area of Material P = Permeance (Unknown) ps = Partial Pressure RH,a = Relative Humidity of Storage Condition (External) RH, = Relative Humidity Corresponding to Initial Moisture Content of Product RHc = Relative Humidity Corresponding to Critical Moisture Content of Product 22 Chapter 4: Data and Results 4.1 Standardizing the Dissolution Procedure Looking at the three calibration curves (Figures 5, 6, and 7; Page 24, Page 24 and Page 25), the average of the three slopes will be used to determine dissolution percentages (ex: Table 11, Page 35) throughout this paper. The specification for calibrator tablet lot “L” shows the dissolution percentages to be between 38% and 44%. Table 2 (Page 25) obviously shows values within this range, so the dissolution apparatus can be considered calibrated and standardized. Table 1. Dissolution Calibration Data Conc (mg/mL) Dilution Absorbance 1/5/99 1/6/99 1 /1 0/99 0.100 100% 0.457 0.460 0.458 0.075 75% 0.346 0.342 0.336 0.050 50% 0.227 0.228 0.224 0.025 25% 0.116 0.115 0.115 “100% Dilution represents 100% Dissolution of 5 mg Prednisone tablets 23 Figure 5. Dissolution Calibration Curve (1/5/99) Dissolution Calibration Curve (1/5/99) 5 0.5 I 0.45 / 0.4 / . 0.35 ' f 2‘ 03 y = 0.4568x + 0.001 ; a. " ' R2 = 0.9998 I 0.25 // l l 0.2 / I 0.15 / I 0.1 l 0.05 0 . e . . 0% 20% 40% 60% 80% 100% 120% Dllutlon 0 1/5/99 -—Linear(1/S/99) Figure 6. Dissolution Calibration Curve (1/6/99) I Dissolution Calibration Curve (1/6/99) 0.5 0.45 0.4 0.35 s = 0.4596x - 0.001 5 0.3 3 R = 0.9999 g 0.25 ‘ 0.2 0.15 0.1 0.05 0 0% 20% 40% 60% 80% 100% 120% DIIUUO" { 0 1/6/1999 —Linear (1/6/1999)_IlI 24 Figure 7. Dissolution Calibration Curve (1/10/99) Absorbance (AU) Dissolution Calibration Curve (1/10/99) 0.5 0.45 / 0.4 / 0.35 y = 0.4576x - 0.0025 / 0.3 R2 = 0.9992 / 0.25 / 0.2 / 0.15 / 0.1 0.05 0% 20 % 40% 60% Dilution 80% 100% 120% 0 1/10/1999 —Linear (1/10/1999) Table 2. USP Calibrator Tablet Dissolution Results Tablettt Absorbance (AU) % Dissolution 1 2 3 4 5 6 0.177 0.181 0.192 0.182 0.185 0.174 39.2 40.1 42.5 40.3 41.0 38.6 *Figure 7 calibration curve was used to determine % dissolution *“USP lot “L” calibrator tablets should be between 38% and 44% dissolution 25 4.2 Moisture Sorption Isotherms Looking at Figure 11 (Page 31), we can see that the isotherm data for all three temperatures follow similar patterns. The data points between 30% RH and 80% RH are well represented by a linear regression (Figure 12, Page 32). Therefore, a linear equation will be used in the shelf life computer model to represent specific moisture sorption isotherms. The isotherms in Figure 11 could not be represented using the GAB model. Since the product will not be exposed to a RH above 80% in our shelf life model, this linear region will be sufficient to represent the product’s sorption isotherms. For example, the product fails dissolution at a storage condition which corresponds to 75% RH. Therefore, concerning the shelf life calculation, the highest RH is 75%. The isotherms were obtained using tablets stored in five-gallon buckets over salt solutions as shown in Table 3. The humidities achieved at 250, 300 and 400 are shown in Table 4 (Page 27). Table 3. Salt Solution RH at Three Temperatures Salt Solution Formula %RH at Stated Temperature 200 250 30C Lithium Chloride LiCl - H20 12.4 12 11.8 Magnesium Chloride MgCIg - 6H20 33.6 33.2 32.8 Magnesium Nitrate Mg(N03)2 - 6H20 54.9 53.4 52 Sodium Nitrite NaNO; 65.3 64.3 63.3 Sodium Chloride NaCl 75.5 75.8 75.6 Ammonium Sulfate (NH.)zSO. 80.6 80.3 80 Potassium Nitrate KNO. 93.2 92 90.7 26 Table 4. Bucket RH Readings for Isotherms [Chamber #4: 25 degrees Celsius (3116199 11:35a) Mercury Thermometer Chart Recorder Digital Chamber Recorder 25C 250 24.7 Hygrometer RH “nominal“ Bucket Dial Reading %RH 12% 94 22.2“ 33% 46 32.75 50% 75 51 65% 85 69.25 75% 54 77.25 80% 75 80.5 90% 63 90.75 Chamber #3: 30 degrees Celsius (3116199 8:00p) Mercury Thermometer Chart Recorder Digital Chamber Recorder 32C 33C 31 .0C Hygrometer RH “nominal“ Bucket Dial Reading %RH 1 2% 20 1 1 .8 33% 59 32.75 50% 77 - 49.75 65% 78 65.5 75% 67 77.75 80% 83 81.25 90% 67 90.25 Chamber #1: 40 degrees Celsius (3116199 11:55p) Mercury Thermometer Chart Recorder Digital Chamber Recorder 400 41 C 40.10 Hygrometer RH “nominal” Bucket Dial Reading %RH 12% 53 13 33% 72 32.25 50% 80 47.5 65% 82 63 75% 77 77.25 80% 88 80 90% 64 88.25 *The reading for this bucket was abnormally high because the seal was faulty. 27 Table 5. Moisture Gain for Prednisone Tablets at 25C Chamber #4: 25 degrees Celsius 311 6199 3118/99 3120/99 3122/99 3129199 415199 1:18p 2:15p 12:55p 2:40p 3:15p 10:25p Bucket/Dish Dish Wt (g) Dish +Smp Dish +Smp Dish +)Smp Dish(;)Smp Dish(+Smp Dish +Smp 12%/1 1.2783 2.7764 2.7771 2.777 2.7774 2.7767 2.7769 33%/2 1 .2854 2.7882 2.7905 2.7905 2.7912 2.7901 2.7901 50%/3 1 .2763 2.7785 2.7847 2.7839 2.7845 2.784 2.7835 60%/4 1 .2801 2.7755 2.785 2.7846 2.7843 2.7842 2.784 75%/5 1 .2716 2.772 2.7849 2.784 2.7834 2.7834 2.7827 80%/6 1 .2778 2.782 2.7965 2.7956 2.7951 2.795 2.7945 90%/7 1.2813 2.7798 2.8089 2.8093 2.8092 2.8092 2.8116 Table 6. Moisture Gain for Prednisone Tablets at 300 Chamber #3: 30 degrees Celsius 311 6199 311 8199 3120/99 3123/99 3129199 416199 8:00p 9:15p 11:00p 12:10a 10:50p 8:05p Bucket/Dish Dish Wt (g) Dish +Smp Dish +Smp Dish +Smp Dish +Smp Dish +Smp Dish +Smp I ) (9) I 12%/1 1 .281 1 2.79806 2.779 2.7788 2.7783 2.7789 2.7785 33%/2 1 .2701 2.7629 2.7633 2.7631 2.7631 2.7633 2.7636 50%/3 1 .2653 2.7657 2.7712 2.7697 2.7694 2.7695 2.7695 60%/4 1 .2687 2.7742 2.7819 2.7809 2.7805 2.7805 2.7804 75%/5 1 .277 2.7743 2.7853 2.7845 2.7839 2.7838 2.7833 80%/6 1.2694 2.7625 2.7744 2.7741 2.7731 2.7731 2.7726 90%/7 1 .2738 2.7728 2.7963 2.796 2.7953 2.7964 2.7966 28 Table 7. Moisture Gain for Prednisone Tablets at 400 lChamber #1: 40 degrees Celsius 3116/99 3/19/99 3/21/99 3123/99 3130/99 417/99 1 1 :55p 121358 122008 1:308 1 :008 9:00p Bucket/Dish Dish Wt (g) Dish +Smp Dish +Smp Dish +Smp Dish +Smp Dish +Smp Dish +Smp 12%/1 1.2779 2.7762 2.773 2.7741 2.7736 2.7738 2.7736 33%/2 1 .2781 2.7818 2.7823 2.7827 2.7824 2.7824 2.7822 50%/3 1.2768 2.7753 2.778 2.7773 2.7773 2.7774 2.7768 60%/4 1 .2829 2.7828 2.7876 2.7879 2.7873 2.7874 2.7873 75%/5 1.2857 2.7922 2.8016 2.8009 2.8 2.8 2.7998 80%/6 1.2736 2.781 2.791 2.7906 2.7897 2.7898 2.7891 90%/7 1.2694 2.7696 2.7888 2.788 2.788 2.7877 2.7883 Figure 8. Moisture Gain for Prednisone Tablets at 250 Moisture Gain (25C) 0035 .------ ._..... ._ .----..__..- --........-_.....--.-........-.-.- --.._._.....-. .. - .._ - -..... _-_-.... .--_.... a 0.025 1 s / 8 0.02 / g 0.015 ‘ ; g 0.01 . / g j I/ 7' , l o 79—— . . . . . I , 0 50 100 150 200 250 300 350 1101901") +12% +33% +50% +60% +75% +80% —+-—90% 29 Figure 9. Moisture Gain for Prednisone Tablets at 300 Moisture Gain (9) Moisture Gain (300) 0.027 0.02 /L ' + ‘ 0.01 7 0.012 ‘ __ I/ "" :i ’ 0.007 - '— r 1 l/ 4 am 'i /// i H F a 3 —Q 1 -0.003 r . . . . . E 0 50 100 150 200 250 300 350 l T.“ (hrs) + 12%: + 33%: + 50% + 600/0 + 75% + 80% —i—- 90% Figure 10. Moisture Gain for Prednisone Tablets at 40C ~————— ._——-_._ __., Moisture Gain (9) -0.005 Moisture Gain (40C) 0.025 0.02 7 .4. 0.015 0.01 - 0.005 - Lieu; 1 00 1 50 200 250 300 350 4‘ 11 me (hrs) + 1 2% + 33% + 50% —l— 60% + 75°/o + 80% —|'— 90% 3O Table 8. Moisture Sorption Isotherm Data MSU isotherm (250) Aw MSU Isotherm (300) Aw MSU Isotherm (40C) Aw EMC EMC EMC {away/1009 Dry Product) Water/100 Dry Product) (gWater/tOOg Dry Product) 0 0 0 0 0 0 4.9613 .2220 4.8858 .1180 4.8593 .1300 5.021 5 .3275 4.9652 .3275 4.9726 .3225 5.1577 .5100 5.0942 .4975 5.0294 4750 5.2790 .6925 5.1883 .6550 5.1235 .6300 5.3816 .7725 5.3094 .7775 5.2432 .7725 5.4404 .8050 5.3527 .8125 5.2821 .8000 6.0600 .9075 5.8433 .9025 5.6359 .8825 Figure 11. Moisture Sorption isotherms 1 Moisture Sorption isotherms ; 10 l A 9 ‘6 l = . l E a. 7 2' O 6 ! 8° 5 - r H " g I‘ O 4 “ (I .3 3 3’ o 2 2 “J 1 I 0. - . - l 0 10 20 30 40 60 70 80 1CD ’ °/ RH ' , O i . 4250 I30C A40C l___ 31 Figure 12. Linear Regression of Moisture Sorption Isotherms EMC (9 Water/ 1009 Dry Prod) Sorption Isotherms (Linear) y = 1.5485x + 4.554 = 0.9794 = 1.4422x + 4.4933 = 0.9899 y :1.1999): + 4.5635 = 0.9717 | l l l l l l l AW 1 0250 I30C A40C j 32 4.3 initial Moisture Content The average of the “dry weight” iMC values, based on 100 grams of dry product, was used in the shelf life calculations. Table 9. Initial Moisture Content of Prednisone 5 mg Tablets IMC Standardization Check: 99.31%, 98.91%, 100.09% Sample Wt (g) "wet' iMC (g'Water/100g Product) 'wet weight“ IMC (g'Water/1009 Product) ”dry weight“ 0.099 4.740 4.976 0.0999 4.700 4.932 0.1005 4.670 4.899 0.0993 4.730 4.965 0.1001 4.730 4.965 Average = 4.947 33 gr . _..4—____ _ . ah... 4.4 Dissolution Testing Dissolution data was gathered for Prednisone tablets at various RH to determine critical conditions at each ICH temperature (25C, SOC, 400). Looking at Table 12 (Page 36), dissolution failures only occurred at RH of 75% or higher for each temperature. So, the critical RH used in shelf life calculations for each iCH temperature was 65%. 65% RH was used as the critical RH, instead of 75%, because the tablets were failing dissolution at a condition somewhere between 65% and 75%. This is one example of conservatism, which is built into the system. Table 12 (Page 36) is a summary table, which reports the average dissolution values. The average dissolution values displayed in the table represent triplicate dissolution testing. So, if one of the average dissolution values in Table 12 (Page 36) is identified as a failure, this means that at least one of the three tablets failed dissolution according to the USP Prednisone monograph, which specifies that dissolution values below 80% are considered failures. These failures within Table 12 (Page 36) are indicated by a dark outline. Table 10. Absorbances of Dissolution Profile Absorbances (AU) Amp # 0 min 10 min 20 min 30 min 40 min 50 min 60 min 1 0 0.279 0.422 0.456 0.464 0.467 0.469 2 0.263 0.415 0.455 0.463 0.467 0.469 3 0 0.326 0.438 0.457 0.462 0.465 0.466 4 0 0.31 0.441 0.459 0.463 0.465 0.468 5 0 0.277 0.426 0.454 0.46 0.467 0.466 6 0 0.261 0.424 0.456 0.465 0.468 0.469 34 Table 11. % Dissolution of Dissolution Profile % Dissolution Samp # 0 min 10 min 20 min 30 min 40 min 50 min 60 min 1 0 61.5 92.7 100.1 101.9 102.5 102.9 2 58.0 91.2 99.9 101.6 102.5 102.9 3 0 71.7 96.2 100.3 101.4 102.1 102.3 4 0 68.2 96.8 100.8 101.6 102.1 102.7 5 0 61.0 93.6 99.7 101.0 102.5 102.3 6 0 57.5 93.1 100.1 102.1 102.7 102.9 Figure 13. Prednisone Tablet Dissolution Profile % Dissoiution Dissolution Profile 30 40 70 Time (min) ( oSmpt lSmp4 lSmpz xSmpS ASmpS oSmp6 35 Table 12. Summary of Dissolution Data (Averages) 25C Average %Dissoiution Values Day %RH 9 12 15 18 21 24 37 44 51 58 50 100 96.98 97.2 97.49 95.82 99.82 97.93 97.13 97.64 96.03 97.49 . 94.72 96.83 65 100 98.58 90.14 95.52 97.34 96.69 96.54 95.89 95.02 97.2 (960319569 95.52 75 100 94.8 91.96 88.03 94 91.89 94.29 86.28 89.92 92.98 86.14 85.77 86.86 80 100 92.69 83.59 88.9 88.03 83.37 87.52 81.91 81.26 81.55 70.12 81.84 84.39 90 100 22.74 6.95 30C Average %Dissolution Values Day %RH 9 12 15 18 21 27 33 40 47 54 33 100 93.27 95.52 93.78 95.52 X X 98 X 95.82 96.98 98.58 50 100 97.64 96.69 101.3 97.64 94.51 98.95 95.31 96.76 94.94 94.36 96.03 96.47 65 100 95.74 96.11 101.3 94.65 94.65 96.25 94.43 94.29 93.27 95.09 90.58 96.47 75 100 95.74 95.6 89.56 88.32 94.36 91.96 91.16 89.19 92.39 86.28 93.41 88.83 80 100 87.59 80.68 84.39 87.23 82.93 84.03 79.66 86.06 73.62 76.24 82.72 83.37 90 100 28.28 40C Average %Dissolution Values Day %RH 9 12 18 21 27 33 40 47 54 12 100 97.93 92.03 97.05 96.11 96.76 X X 96.83 33 100 96.33 97.56 96.83 96.03 97.78 X X 96.18 50 100 93.92 96.11 96.11 94.72 97.56 95.74 93.71 95.89 93.63 92.1 95.09 65 100 96.03 97.93 98 96.91 95.23 96.03 94.51 96.4 91.08 91.45 94.14 75 100 96.03 84.03 89.19 90.14 84.61 88.83 84.68 83.88 82.72 80.82 85.26 80 100 91.89 78.2 80.17 81.11 62.05 65.1 75.22 71.87 73.69 52.95 72.82 90 100 41.52 = Failure (at Ieast1 of 3) = not tested i l i T *Appendix A contains all of the raw dissolution data. “Each value in this table is an average of three dissolution tests. A failure is defined by the USP official monograph for Prednisone tablets as not less than 80% dissolved in 30 minutes. 36 4.5 Statistical Analysis Each sampling point was tested in triplicate nearly every three days for approximately two months. Appendix A contains raw dissolution data and statistical analysis for every testing point. First of all, as the raw dissolution data is reviewed for each storage temperature, dissolution failures (< 80% dissolution) only occur at RH of 75% or higher. This means that we are reaching our critical condition somewhere between 65% and 75% RH. The conservative approach is to conclude 65% to be the critical RH. The critical moisture content is then determined by using the corresponding isotherm (Figure 12, Page 32). To reinforce this conclusion, the variability of the individual dissolution testing points can be analyzed. Table 14 (Page 46) lists the standard deviations for the dissolution testing at each test interval. Looking at the average of the standard deviations for each RH, a significant increase in variation occurs at 75%. This corresponds to the dissolution failures previously mentioned. As the testing conditions become more severe (higher RH and temperatures), the Prednisone tablets are less likely to readily disintegrate in the dissolution medium. In fact, for most of the dissolution failures (Appendix A, Page 48), especially for samples stored at 90% RH, large chunks of tablet were found in the bottom of the dissolution vessel when samples were taken at 30 minutes. These dissolution failures were accompanied by high variability between dissolution values taken at the same testing intervals. 37 Table 13. Summary of Dissolution Data (Standard Deviations) 25C Dissolution Testing: Standard Deviations from Triplicate Testing Day %RH 3 6 9 12 15 18 21 24 37 44 51 58 Ave 50 1.957 0.504 0.655 2.531 1.668 1.135 0.550 1.032 2.605 6.839 4.314 3.033 2.235 65 4.008 7.745 0.218 0.504 3.859 1.857 1.120 1.077 1.580 3.106 1.316 0.756 2.262 75 1.334 2.241 11.722 2.461 3.720 1.668 6.150 2.395 1.120 10.122 8.211 6.602 4.812 80 1.364 5.282 2.559 5.456 6.685 6.850 5.057 11.630 11.446 3.938 4.869 3.431 5.714 30C Dissolution Testing: Standard Deviations from Triplicate Testing Day %RH 3 6 9 12 15 18 21 27 33 40 47 54 Ave 50 0.549 1.486 5.412 0.630 3.241 0.882 1.941 1.778 1.639 3.385 2.435 0.882 2.022 65 1.155 2.405 0.334 3.725 5.575 2.314 2.150 0.909 4.476 0.952 5.460 1.765 2.602 75 1.513 2.531 10.374 8.132 2.605 0.767 3.712 5.677 0.882 3.314 0.882 2.355 3.562 80 2.605 11.347 3.297 4.560 6.537 5.929 8.816 4.685 9.009 3.363 1.696 2.782 5.386 400 Dissolution Testing: Standard Deviations from Triplicate Testing Dav %RH 3 6 9 1 2 15 1 8 21 27 33 40 47 54 Ave 50 4.745 2.335 2.899 2.355 1.216 1.099 5.689 1.077 0.985 1.120 2.531 1.891 2.329 65 3.636 1.513 2.605 1.279 1.404 1.981 2.559 4.087 1.216 1.421 1.203 0.549 1.954 75 3.285 9.911 5.571 3.278 8.147 9.919 3.550 7.269 4.369 8.953 4.269 5.614 6.176 80 1.316 4.582 1.580 8.893 15.362 8.083 10.420 9.965 7.029 6.626 6.078 3.172 6.926 38 Chapter 5: Conclusions The calculations below were accomplished using the shelf life equation (Eq 6) described on page 22. Using the data within the sections of Chapter 4, permeance values (P) were calculated given a desired shelf life (t). The permeance values were then used to determine package options. Blister calculations are listed first. We RH TesthJB—"M t = 730 days (2 years) [desired shelf life] I = 1 mil (Use a value of 1 for blisters) W = 0.1 g per tablet B = 1.5485 (unitless) (Reference Figure 11, Page 31) A = 1 m2 (Use a value of 1 for blisters) P = Permeance (Unknown) ps = 23.756 mm Hg RHe = 75% (RH of storage conditions) RH; = 25.4% (RH generated by shelf life computer model using the IMC) RHc = 65% (Same RH for all three temperatures) 730 days = (1 mil*0.1g*1 .5485/1m2*P*23.756mmHg)*ln[(.75—.254)/(.75—.65)] P = 1 .43 * 10'5 glday*cavity*mmHg 39 300 175% RH Testing (Blisters) t = 365 days (1 year) [desired shelf life] I = 1 mil (Use a value of 1 for blisters) W = 0.1 g per tablet B = 1.4422 (unitless) (Reference Figure 11, Page 31) A = 1 m2 (Use a value of 1 for blisters) P = Permeance (Unknown) p5 = 31.824 mm Hg RHe = 75% (RH of storage conditions) RH; = 31.5% (RH generated by shelf life computer model using the lMC) RHc = 65% (Same RH for all three temperatures) 365 days = (1 mil*0.‘1g*1 .442211m2*P*31 .824mmHg)*in[(.75—.315)/(.75-.65)] P = 1.83 * 10'5 glday’cavity*mmHg 4O 40C 175% RH Testing (Blisters) t = 180 days (6 months) [desired shelf life] i = 1 mil (Use a value of 1 for blisters) W = 0.1 g per tablet B = 1.2000 (unitless) (Reference Figure 11, Page 31) A = 1 m2 (Use a value of 1 for blisters) P = Permeance (Unknown) 0, = 55.324 mm Hg RHe = 75% (RH of storage conditions) RHi = 32.2% (RH generated by shelf life computer model using the IMC) RHc = 65% (Same RH for all three temperatures) 180 days = (1mil*0.1g*1.2000/1m2*P*55.324mmHg)*ln[(.75-.322)1(.75-.65)] P = 1.75 * 10'5 glday*cavity*mmHg Looking at the 25C (room temperature) shelf life calculation for blisters, 730 days (two years) was used as the desired shelf life. For marketed products, this is a typical shelf life to use during the initial stages of development for room temperature or real-time stability. For the 300 (accelerated) blister calculation, 365 days (one year) was used as the desired shelf life. As a rule of thumb, if packaged product passes analytical testing after one year at 300, the packaged product can be assumed to pass two years at 25C. For similar reasons, the 40C (accelerated) calculations use 180 days (six months) as the desired shelf life. if 41 the packaged product passes analytical testing after six months at 40C, the packaged product can be assumed to pass two years at 250. Using the 400 permeation result as an example, blister materials which have a permeance value below 1.75 * 10-5 g/day‘cavity*mmHg (tested at 40C/ 75%RH) will be packaging options for this Prednisone product. The calculated permeance value identifies a specific level of moisture, which will initiate product failure within a package. For example, PVC is a relatively inexpensive material, which has a high permeance to moisture. Using PVC blisters for a developmental product is an excellent way to reduce material costs once the product is packaged at high volumes for market. A typical permeance value for PVC blisters at 40C / 75% RH is 4.57 * 10'5 g/day‘cavity*mmHg (Eli Lilly and Company, 2000). Since this value is higher than the calculated permeance value for blisters at 40C, PVC may not be an option, and a more expensive, higher barrier material will be recommended. Aciar is a popular high barrier blister used in the pharmaceutical industry. A typical permeance value for 0.6mii Aciar blisters at 40C / 75% RH is 3.88 "’ 10'6 g/day*cavity*mmHg (Eli Lilly and Company, 2000). Reviewing the calculated permeance value for blisters at 40C, the level of moisture protection received from 0.6mii Aclar is sufficient. Pharmaceutical companies typically use high density polyethylene (HDPE) containers when a solid oral product requires a bottle for packaging. The Prednisone tablets being used for this study were supplied in HDPE bottles. These bottles contained 1000 tablets and were approximately 17000 in volume. ‘7 The permeance calculations at three conditions for the bottles described above are as follows. at; 175% RH Testing (Bottles) t = 730 days (2 years) [desired shelf life] I = 34 mil W = 100 g (0.1 g per tablet, 1000 tablets per bottle) B = 1.5485 (unitless) (Reference Figure 11, Page 31) A = 0.03m2 (Area of bottle walls) P = Permeance (Unknown) p5 = 23.756 mm Hg RHe = 75% (RH of storage conditions) RHi = 25.4% (RH generated by shelf life computer model using the lMC) RHc = 65% (Same RH for all three temperatures) 730 days = (34mil‘1009*1.5485/0.03m2*P*23.756mmHg)*ln[(.75—.254)/(.75—.65)] P = 16.2 g/day*bottle*mmH9 43 39g 75% RH Testing (Bottles) t = 365 days (1 year) [desired shelf life] i = 34 mil W = 100 g (0.1 g per tablet, 1000 tablets per bottle) B = 1.4422 (unitless) (Reference Figure 11, Page 31) A = 0.03 m2 (Area of bottle walls) P = Permeance (Unknown) p5: 31.824 mm Hg RHa == 75% (RH of storage conditions) RH. = 31.5% (RH generated by shelf life computer model using the lMC) RHc = 65% (Same RH for all three temperatures) 365 days = (34mi|*1009*1 .442210.03m2*P*31.824mmHg)*in[(.75—.315)1(.75—.65)] P = 20.7 glday*bottle*mmHg < ““1 .5 ’ 400 175% RH Testing (Bottles) t = 180 days (6 months) [desired shelf life] I: 34 mil W = 100 g (0.1 g per tablet, 1000 tablets per bottle) B = 1.2000 (unitless) (Reference Figure 11, Page 31) A = 0.03 m2 (Area of bottle walls) mar ~ P = Permeance (Unknown) p3: 55.324 mm Hg “at . RHe = 75% (RH of storage conditions) RH; = 32.2% (RH generated by shelf life computer model using the lMC) RHc = 65% (Same RH for all three temperatures) 180 days = (34mil*1009*1.2000/0.03m2*P*55.324mmHg)*ln[(.75—.322)1(.75-.65)] P = 19.9 glday‘bottle*mmHg A typical HDPE bottle (34mil thickness and area equal to 0.03m2) at 17000 will have a permeance value of approximately 0.04 g1day*bottle*mmHg at 4001 75% RH (Eli Lilly and Company, 2000). Comparing this value to the bottle permeation results for 400, 0.04 is much lower than 19.9. The level of protection for this product in a 1000 count HDPE bottle with minimal head space is very high. However, as the bottle count decreases, the permeation value in the shelf life calculation will decrease. So, a lower count in the same bottle will ultimately be less protected because there are fewer tablets to share the moisture permeating into the bottle. 45 The shelf life calculations have provided packaging options for this Prednisone product for blisters and bottles. Concerning blisters, this product may not meet stability requirements in PVC blisters, but should be protected sufficiently in 0.6 mil Aclar. For bottles, higher count bottle presentations (bulk) in typical HDPE bottles should provide sufficient protection. However, as the product count significantly decreases for a specific bottle presentation, permeation values should be reviewed closely. Table 14. Summary of Calculated Permeance Values Condition Package Permeance (glday‘package'mmHg) Desired Shelf Life 250175%RH Blister 1.43 ' 10" 2 years 300/75%RH Blister 1.83 " 10'5 1 year 400/75%RH Blister 1.75 * 10*" 6 months 250/75%RH Bottle 16.2 2 years SOC/75%RH Bottle 20.7 1 year 4OCf75%RH Bottle 19.9 6 months These packaging calculations are not meant to replace any type of product/package stability test. However, the information gathered and calculations made in such a study, especially for early development products, can identify packaging Options for early phase stability studies. For example, instead of using four or five blister materials in initial product/package stability testing, shelf life modeling can narrow the choices down to two or three options, which can significantly reduce development costs. 46 Chapter 6: Recommendations for Future Work My recommendation for future work is to expand the existing shelf life model at the School of Packaging to include other packaging components. For example, isotherms can be developed for desiccant packages and bottle fillers (ex: cotton), which compete with the product to absorb moisture. The moisture contents of these components can be accounted for within the model, similar to the product moisture content. Packaging components such as fillers and desiccant are popular materials in the pharmaceutical industry. Modeling a complex system such as a bottle containing product, cotton and desiccant, is a realistic packaging option used in industry. 47 Appendix A 250 Dissolution Values (Raw Data and Statistics) %Dlssolutlon Determination (25C) ABS(AU) . %Dissolution %RH #1 #2 #3 #1 #2 #3 50 0.437 0.452 0.436 95.96 99.24 95.74 Mean = 0.442 STD = 0.00896 Mean = 96.980 STD = 65 0.428 0.457 0.462 94.00 100.33 101.42 Mean = 0.449 STD = 0.0184 Mean = 98.581 STD = 75 0.437 0.433 0.425 95.96 95.09 93.34 Mean = 0.432 STD = 0.0061 Mean = 94.796 STD = 80 0.415 0.427 0.424 91.16 93.78 93.12 Mean = 0.422 STD = 0.0062 Mean = 92.686 STD = 90 0.113 0.097 0.095 25.22 21.72 21.29 Mean 2 0.102 STD = 0.0099 Mean = 22.744 STD = Time(days)= 3 Calibration Curve: "y=0.458 x - 0.0025” Table 15. 250 Raw Dissolution Data and Statistics (Day3) %Dlssolutlon Determination (25C) ABS(AU) %Dissolution %RH #1 #2 #3 #1 #2 #3 50 0.44 0.444 0.444 96.62 97.49 97.49 Mean = 0.443 STD = 0.00231 Mean = 97.198 STD = 65 0.442 0.417 0.372 97.05 91.59 81.77 Mean = 0.410 STD = 0.0355 Mean = 90.138 STD = 75 0.416 0.43 0.41 91.38 94.43 90.07 Mean = 0.419 STD = 0.0103 Mean = 91.958 STD = 80 0.389 0.353 0.399 85.48 77.62 87.66 Mean = 0.380 STD = 0.0242 Mean = 83.588 STD = Time(days)= 6 Calibration Curve: "y=0.458 x - 0.0025" Table 16. 250 Raw Dissolution Data and Statistics (Day6) 48 1.95696 4.00820 1.33408 1 .36354 2.15410 0.50424 7.74520 2.24087 5.28246 %Dissoiution Determination (25C) ABS(AU) %Dissolution %RH #1 #2 #3 #1 #2 #3 50 0.444 0.447 0.441 97.49 98.14 96.83 Mean = 0.444 STD = 0.00300 Mean = 97.489 STD = 65 0.436 0.434 0.435 95.74 95.31 95.52 Mean = 0.435 STD = 0.0010 Mean = 95.524 STD = 75 0.426 0.437 0.339 93.56 95.96 74.56 Mean = 0.401 STD = 0.0537 Mean = 88.028 STD = 80 0.396 0.4 0.418 87.01 87.88 91.81 Mean = 0.405 STD = 0.0117 Mean = 88.901 STD = Time(days)= 9 Calibration Curve: 'y=0.458 x - 0.0025” Table 17. 250 Raw Dissolution Data and Statistics (Day9) %Dlssolutlon Determination (25C) ABS(AU) %Dissolution %RH #1 #2 #3 #1 #2 #3 50 0.424 0.447 0.438 93.12 98.14 96.18 Mean = 0.436 STD = 0.01159 Mean = 95.815 STD = 65 0.442 0.442 0.446 97.05 97.05 97.93 Mean = 0.443 STD = 0.0023 Mean = 97.344 STD = 75 0.415 0.435 0.434 91 .16 95.52 95.31 Mean = 0.428 STD = 0.0113 Mean = 93.996 STD = 80 0.379 0.428 0.395 83.30 94.00 86.79 Mean = 0.401 STD = 0.0250 Mean = 88.028 STD = Time(days)= 12 Calibration Curve: 'y=0.458 x - 0.0025“ Table 18. 250 Raw Dissolution Data and Statistics (Day12) 49 0.65502 0.21834 11.72213 2.55872 2.53062 0.50424 2.46057 5.45560 %Dissoiution Determination (25C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 50 0.463 0.453 0.448 101.64 99.45 98.36 Mean = 0.455 STD = 0.00764 Mean = 99.818 STD = 65 0.449 0.452 0.42 98.58 99.24 92.25 Mean = 0.440 STD = 0.0177 Mean = 96.689 STD = 75 0.402 0.417 0.436 88.32 91.59 95.74 Mean = 0.418 STD = 0.0170 Mean = 91.885 STD = 80 0.344 0.396 0.398 75.66 87.01 87.45 Mean = 0.379 STD = 0.0306 Mean = 83.370 STD = Time(days)= 15 Calibration Curve: 'y=0.458 x - 0.0025“ Table 19. 250 Raw Dissolution Data and Statistics (Day15) %Dissoiution Determination (250) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 50 0.452 0.443 0.443 99.24 97.27 97.27 Mean = 0.446 STD = 0.00520 Mean = 97.926 STD = 65 0.431 0.448 0.44 94.65 98.36 96.62 Mean = 0.440 STD = 0.0085 Mean = 96.543 STD = 75 0.421 0.431 0.436 92.47 94.65 95.74 Mean = 0.429 STD = 0.0076 Mean = 94.287 STD = 80 0.375 0.434 0.386 82.42 95.31 84.83 Mean = 0.398 STD = 0.0314 Mean = 87.518 STD = Time(days)= 18 Calibration Curve: 'y=0.458 x - 0.0025" Table 20. 25C Raw Dissolution Data and Statistics (Day18) 50 1 .66760 3.85872 3.72034 6.68469 1.13453 1 .85697 1 .66760 6.85024 We '3‘ . %Dissoiution Determination (25C) 377m -.r. {‘1" ‘ . . I ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 50 0.442 0.44 0.445 97.05 96.62 97.71 Mean = 0.442 STD = 0.00252 Mean = 97.125 STD = 0.54948 65 0.431 0.441 0.438 94.65 96.83 96.18 Mean = 0.437 STD = 0.0051 Mean = 95.888 STD = 1.12044 70 0.363 0.419 0.396 79.80 92.03 87.01 Mean = 0.393 STD = 0.0281 Mean = 86.281 STD = 6.14594 80 0.392 0.379 0.347 86.14 83.30 76.31 Mean = 0.373 STD = 0.0232 Mean = 81.914 STD = 5.05652 Time(days)= 21 Calibration Curve: 'y=0.458 x - 0.0025" Table 21. 25C Raw Dissolution Data and Statistics (Day21) %Dissoiution Determination (250) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 50 0.441 0.45 0.443 96.83 98.80 97.27 Mean = 0.445 STD = 0.00473 Mean = 97.635 STD = 1.03184 65 0.435 0.436 0.427 95.52 95.74 93.78 Mean = 0.433 STD = 0.0049 Mean = 95.015 STD = 1.07705 70 0.397 0.413 0.418 87.23 90.72 91.81 Mean = 0.409 STD = 0.0110 Mean = 89.920 STD = 2.39512 80 0.383 0.415 0.311 84.17 91.16 68.45 Mean = 0.370 STD = 0.0533 Mean = 81.259 STD = 11.63027 Time(days)= 24 Calibration Curve: 'y=0.458 x - 0.0025” Table 22. 250 Raw Dissolution Data and Statistics (Day24) 51 %Dlssolutlon Determination (25C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 50 0.432 0.429 0.451 94.87 94.21 99.02 Mean = 0.437 STD = 0.01193 Mean = 96.033 STD = 65 0.439 0.451 0.438 96.40 99.02 96.18 Mean = 0.443 STD = 0.0072 Mean = 97.198 STD = 75 0.429 0.419 0.422 94.21 92.03 92.69 Mean = 0.423 STD = 0.0051 Mean = 92.977 STD = 80 0.313 0.415 0.385 68.89 91 .16 84.61 Mean = 0.371 STD = 0.0524 Mean = 81.550 STD = Time(days)= 37 Calibration Curve: 'y=0.458 x - 0.0025“ Table 23. 250 Raw Dissolution Data and Statistics (Day37) %Dissoiution Determination (250) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 50 0.408 0.465 0.459 89.63 102.07 100.76 Mean = 0.444 STD = 0.03132 Mean = 97.489 STD = 65 0.444 0.421 0.447 97.49 92.47 98.14 Mean = 0.437 STD = 0.0142 Mean = 96.033 STD = 75 0.339 0.412 0.425 74.56 90.50 93.34 Mean = 0.392 STD = 0.0464 Mean = 86.135 STD = 80 0.336 0.32 0.3 73.91 70.41 66.05 Mean = 0.319 STD = 0.0180 Mean = 70.124 STD = 90 0.028 0.028 0.032 6.66 6.66 7.53 Mean = 0.029 STD = 0.0023 Mean = 6.951 STD = Time(days)= 44 Calibration Curve: 'y=0.458 x - 0.0025" Table 24. 250 Raw Dissolution Data and Statistics (Day44) 52 2.60488 1.57951 1.12044 11.44571 6.83863 3.10576 10.12168 3.93821 0.50424 li- 1.. %Dissoiution Determination (250) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 50 0.435 0.41 0.449 95.52 90.07 98.58 Mean = 0.431 STD = 0.01976 Mean = 94.723 STD = 65 0.446 0.441 0.434 97.93 96.83 95.31 Mean = 0.440 STD = 0.0060 Mean = 96.689 STD = 75 0.376 0.362 0.433 82.64 79.59 95.09 Mean = 0.390 STD = 0.0376 Mean = 85.771 STD = 80 0.347 0.389 0.381 76.31 85.48 83.73 Mean = 0.372 STD = 0.0223 Mean = 81.841 STD = Time(days)= 51 Calibration Curve: 'y=0.458 x - 0.0025" Table 25. 250 Raw Dissolution Data and Statistics (Day51) %Dissoiution Determination (25C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 12 0.437 0.448 0.448 95.96 98.36 98.36 Mean = 0.444 STD = 0.00635 Mean = 97.562 STD = 33 0.446 0.452 0.448 97.93 99.24 98.36 Mean = 0.449 STD = 0.0031 Mean = 98.508 STD = 50 0.425 0.448 0.45 93.34 98.36 98.80 Mean = 0.441 STD = 0.0139 Mean = 96.834 STD = 65 0.433 0.433 0.439 95.09 95.09 96.40 Mean = 0.435 STD = 0.0035 Mean = 95.524 STD = 75 0.407 0.361 0.418 89.41 79.37 91.81 Mean = 0.395 STD = 0.0302 Mean = 86.863 STD = 80 0.401 0.381 0.37 88.10 83.73 81.33 Mean = 0.384 STD = 0.0157 Mean = 84.389 STD = Time(days)= 58 Calibration Curve: 'y=0.458 x - 0.0025" Table 26. 250 Raw Dissolution Data and Statistics (Day58) 53 4.31372 1.31609 8.21127 4.86921 1 .38665 0.66704 3.03328 0.75635 6.60217 3.43149 30C Dissolution Values (Raw Data and Statistics) %Dissoiution Determination (30C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 33 0.443 0.402 0.429 97.27 88.32 94.21 Mean = 0.425 STD = 0.02084 Mean = 93.268 STD = 50 0.442 0.445 0.447 97.05 97.71 98.14 Mean = 0.445 STD = 0.0025 Mean = 97.635 STD = 65 0.432 0.442 0.434 94.87 97.05 95.31 Mean = 0.436 STD = 0.0053 Mean = 95.742 STD = 75 0.432 0.444 0.432 94.87 97.49 94.87 Mean = 0.436 STD = 0.0069 Mean = 95.742 STD = 80 0.407 0.404 0.385 89.41 88.76 84.61 Mean = 0.399 STD = 0.0119 Mean = 87.591 STD = 90 0.146 0.087 0.148 32.42 19.54 32.86 Mean = 0.127 STD = 0.0347 Mean = 28.275 STD = Time(days)= 3 Calibration Curve: 'y=0.458 x - 0.0025" Table 27. 300 Raw Dissolution Data and Statistics (Day3) %Dissoiution Determination (300) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 12 0.442 0.408 0.454 97.05 89.63 99.67 Mean = 0.435 STD = 0.02386 Mean = 95.451 STD = 33 0.417 0.456 0.432 91.59 100.11 94.87 Mean = 0.435 STD = 0.0197 Mean = 95.524 STD = 50 0.438 0.448 0.435 96.18 98.36 95.52 Mean = 0.440 STD = 0.0068 Mean = 96.689 STD = 65 0.437 0.449 0.427 95.96 98.58 93.78 Mean = 0.438 STD = 0.0110 Mean = 96.106 STD = 75 0.423 0.437 0.446 92.90 95.96 97.93 Mean = 0.435 STD = 0.0116 Mean = 95.597 STD = 80 0.406 0.308 0.387 89.19 67.79 85.04 Mean = 0.367 STD = 0.0520 Mean = 80.677 STD = Time(days)= 6 Calibration Curve: 'y=0.458 x - 0.0025" Table 28. 300 Raw Dissolution Data and Statistics (Day6) 54 4.55036 0.54948 1.15535 1.51271 2.60488 7.56669 5.20976 4.29527 1 .48621 2.40505 2.53062 11.34741 1‘ %Dissoiution Determination (306) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 12 0.45 0.441 0.437 98.80 96.83 95.96 Mean = 0.443 STD = 0.00666 Mean = 97.198 STD = 33 0.423 0.429 0.429 92.90 94.21 94.21 Mean = 0.427 STD = 0.0035 Mean = 93.777 STD = 50 0.433 0.479 0.472 95.09 105.13 103.60 Mean = 0.461 STD = 0.0248 Mean = 101.274 STD = 65 0.461 0.463 0.46 101.20 101.64 100.98 Mean = 0.461 STD = 0.0015 Mean = 101.274 STD = 75 0.353 0.439 0.431 77.62 96.40 94.65 Mean = 0.408 STD = 0.0475 Mean = 89.556 STD = 80 0.382 0.4 0.37 83.95 87.88 81.33 Mean = 0.384 STD = 0.0151 Mean = 84.389 STD = Time(days)= 9 Calibration Curve: 'y=0.458 x - 0.0025" Table 29. 30C Raw Dissolution Data and Statistics (Day9) %Dissoiution Determination (30C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 12 0.439 0.45 0.431 96.40 98.80 94.65 Mean = 0.440 STD = 0.00954 Mean = 96.616 STD = 33 0.436 0.43 0.439 95.74 94.43 96.40 Mean = 0.435 STD = 0.0046 Mean = 95.524 STD = 50 0.443 0.448 0.443 97.27 98.36 97.27 Mean = 0.445 STD = 0.0029 Mean = 97.635 STD = 65 0.417 0.426 0.45 91.59 93.56 98.80 Mean = 0.431 STD = 0.0171 Mean = 94.651 STD = 75 0.359 0.423 0.424 78.93 92.90 93.12 Mean = 0.402 STD = 0.0372 Mean = 88.319 STD = 80 0.387 0.421 0.383 85.04 92.47 84.17 Mean = 0.397 STD = 0.0209 Mean = 87.227 STD = Time(days)= 12 Calibration Curve: "y=0.458 x - 0.0025" Table 30. SOC Raw Dissolution Data and Statistics (Day12) 55 1 .45378 0.75635 5.41174 0.33352 1 0.37367 3.29687 2.08284 1 .00056 0.63030 3.72461 8.13154 4.55909 %Dissoiution Determination (30C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 50 0.434 0.414 0.443 95.31 90.94 97.27 Mean = 0.430 STD = 0.01484 Mean = 94.505 STD = 65 0.437 0.453 0.403 95.96 99.45 88.54 Mean = 0.431 STD = 0.0255 Mean = 94.651 STD = 75 0.426 0.42 0.443 93.56 92.25 97.27 Mean = 0.430 STD = 0.0119 Mean = 94.360 STD = 80 0.398 0.343 0.391 87.45 75.44 85.92 Mean = 0.377 STD = 0.0299 Mean = 82.933 STD = Time(days)= 15 Calibration Curve: 'y=0.458 x - 0.0025" Table 31. 300 Raw Dissolution Data and Statistics (Day15) %Dissoiution Determination (30C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 50 0.447 0.45 0.455 98.14 98.80 99.89 Mean = 0.451 STD = 0.00404 Mean = 98.945 STD = 65 0.427 0.448 0.44 93.78 98.36 96.62 Mean = 0.438 STD = 0.0106 Mean = 96.252 STD = 75 0.419 0.422 0.415 92.03 92.69 91 .16 Mean = 0.419 STD = 0.0035 Mean = 91.958 STD = 80 0.351 0.397 0.399 77.18 87.23 87.66 Mean = 0.382 STD = 0.0272 Mean = 84.025 STD = Time(days)= 18 Calibration Curve: 'y=0.458 x - 0.0025" Table 32. 300 Raw Dissolution Data and Statistics (Day18) 56 3.24097 5.57517 2.60488 6.53686 0.88241 2.31414 0.76679 5.92880 “3 ‘. ’d‘. %Dissoiution Determination (30C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 12 0.45 0.455 0.437 98.80 99.89 95.96 Mean = 0.447 STD = 0.00929 Mean = 98.217 STD = 33 0.437 0.453 0.449 95.96 99.45 98.58 Mean = 0.446 STD = 0.0083 Mean = 97.999 STD = 50 0.437 0.441 0.424 95.96 96.83 93.12 Mean = 0.434 STD = 0.0089 Mean = 95.306 STD = 65 0.427 0.441 0.422 93.78 96.83 92.69 Mean = 0.430 STD = 0.0098 Mean = 94.432 STD = 75 0.415 0.398 0.432 91 .16 87.45 94.87 Mean = 0.415 STD = 0.0170 Mean = 91.157 STD :- 80 0.39 0.381 0.316 85.70 83.73 69.54 Mean = 0.362 STD = 0.0404 Mean = 79.658 STD = Time(days)= 21 Calibration Curve: “'y=0.458 x - 0.0025" Table 33. 300 Raw Dissolution Data and Statistics (Day21) %Dissoiution Determination (30C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 50 0.435 0.437 0.45 95.52 95.96 98.80 Mean = 0.441 STD = 0.00814 Mean = 96.761 STD = 65 0.426 0.434 0.428 93.56 95.31 94.00 Mean = 0.429 STD = 0.0042 Mean = 94.287 STD = 75 0.406 0.38 0.432 89.19 83.52 94.87 Mean = 0.406 STD = 0.0260 Mean = 89.192 STD = 80 0.367 0.406 0.402 80.68 89.19 88.32 Mean = 0.392 STD = 0.0215 Mean = 86.063 STD = Time(days)= 27 Calibration Curve: 'y=0.458 x - 0.0025“ Table 34. 30C Raw Dissolution Data and Statistics (Day27) 57 2.02873 1.81805 1 .94065 2.15041 3.71179 8.81602 1 .77828 0.90902 5.67686 4.68458 %Dissoiution Determination (30C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 12 0.401 0.435 0.432 88.10 95.52 94.87 Mean = 0.423 STD = 0.01882 Mean = 92.831 STD = 4.10999 33 0.446 0.459 0.404 97.93 100.76 88.76 Mean = 0.436 STD = 0.0287 Mean = 95.815 STD = 6.27642 50 0.432 0.425 0.44 94.87 93.34 96.62 Mean = 0.432 STD = 0.0075 Mean = 94.942 STD = 1.63877 65 0.436 0.437 0.401 95.74 95.96 88.10 Mean = 0.425 STD = 0.0205 Mean = 93.268 STD = 4.47643 75 0.417 0.42 0.425 91.59 92.25 93.34 Mean = 0.421 STD = 0.0040 Mean = 92.394 STD = 0.88241 80 0.373 0.34 0.291 81.99 74.78 64.08 Mean = 0.335 STD = 0.0413 Mean = 73.617 STD = 9.00859 Time(days)= 33 Calibration Curve: 'y=0.458 x - 0.0025“ Table 35. 300 Raw Dissolution Data and Statistics (Day33) %Dissoiution Determination (3°C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 12 0.45 0.439 0.448 98.80 96.40 98.36 Mean = 0.446 STD = 0.00586 Mean = 97.853 STD = 1.27936 33 0.439 0.443 0.443 96.40 97.27 97.27 Mean = 0.442 STD = 0.0023 Mean = 96.980 STD = 0.50424 50 0.412 0.436 0.441 90.50 95.74 96.83 Mean = 0.430 STD = 0.0155 Mean = 94.360 STD = 3.38487 65 0.428 0.436 0.435 94.00 95.74 95.52 Mean = 0.433 STD = 0.0044 Mean = 95.087 STD = 0.95172 75 0.39 0.409 0.379 85.70 89.85 83.30 Mean = 0.393 STD = 0.0152 Mean = 86.281 STD = 3.31370 80 0.316 0.35 0.374 69.54 76.97 82.21 Mean = 0.347 STD = 0.0291 Mean = 76.237 STD = 6.36317 Time(days)= 40 Calibration Curve: 'y=0.458 x - 0.0025" Table 36. 300 Raw Dissolution Data and Statistics (Day40) 58 %Dissoiution Determination (300) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 50 0.429 0.45 0.433 94.21 98.80 95.09 Mean = 0.437 STD = 0.01115 Mean = 96.033 STD = 2.43460 65 0.395 0.441 0.401 86.79 96.83 88.10 Mean = 0.412 STD = 0.0250 Mean = 90.575 STD = 5.45997 75 0.421 0.429 0.426 92.47 94.21 93.56 Mean = 0.425 STD = 0.0040 Mean = 93.413 STD = 0.88241 80 0.37 0.374 0.385 81.33 82.21 84.61 Mean = 0.376 STD = 0.0078 Mean = 82.715 STD = 1.69595 Time(days)= 47 Calibration Curve: 'y=0.458 x - 0.0025“ Table 37. 300 Raw Dissolution Data and Statistics (Day47) %Dissoiution Determination (300) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 12 0.437 0.432 0.448 95.96 94.87 98.36 Mean = 0.439 STD = 0.00819 Mean = 96.397 STD = 1.78719 33 0.452 0.447 0.448 99.24 98.14 98.36 Mean = 0.449 STD = 0.0026 Mean = 98.581 STD = 0.57767 50 0.443 0.435 0.44 97.27 95.52 96.62 Mean = 0.439 STD = 0.0040 Mean = 96.470 STD = 0.88241 65 0.43 0.444 0.444 94.43 97.49 97.49 Mean = 0.439 STD = 0.0081 Mean = 96.470 STD = 1.76483 75 0.392 0.412 0.409 86.14 90.50 89.85 Mean = 0.404 STD = 0.0108 Mean = 88.828 STD = 2.35498 80 0.371 0.373 0.394 81.55 81.99 86.57 Mean = 0.379 STD = 0.0127 Mean = 83.370 STD = 2.78188 Time(days)= 54 Calibration Curve: 'y=0.458 x - 0.0025“ Table 38. 300 Raw Dissolution Data and Statistics (Day54) 59 4OC Dissolution Values (Raw Data and Statistics) %Dissoiution Determination (400) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 12 0.438 0.45 0.45 96.18 98.80 98.80 Mean = 0.446 STD = 0.00693 Mean = 97.926 STD = 33 0.432 0.45 0.434 94.87 98.80 95.31 Mean = 0.439 STD = 0.0099 Mean = 96.325 STD = 50 0.444 0.403 0.436 97.49 88.54 95.74 Mean = 0.428 STD = 0.0217 Mean = 93.923 STD = 65 0.424 0.456 0.432 93.12 100.11 94.87 Mean = 0.437 STD = 0.0167 Mean = 96.033 STD = 75 0.445 0.447 0.42 97.71 98.14 92.25 Mean = 0.437 STD = 0.0150 Mean = 96.033 STD = 80 0.424 0.419 0.412 93.12 92.03 90.50 Mean = 0.418 STD = 0.0060 Mean = 91.885 STD = 90 0.206 0.169 0.188 45.52 37.45 41.59 Mean = 0.188 STD = 0.0185 Mean = 41.521 STD .-. Time(days)= 3 Calibration Curve: 'y=0.458 x - 0.0025" Table 39. 400 Raw Dissolution Data and Statistics (Day3) %Dissoiution Determination (40C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 12 0.388 0.429 0.44 85.26 94.21 96.62 Mean = 0.419 STD = 0.02740 Mean = 92.031 STD = 33 0.437 0.461 0.435 95.96 101.20 95.52 Mean = 0.444 STD = 0.0145 Mean = 97.562 STD = 50 0.426 0.44 0.447 93.56 96.62 98.14 Mean = 0.438 STD = 0.0107 Mean = 96.106 STD = 65 0.438 0.45 0.45 96.18 98.80 98.80 Mean = 0.446 STD = 0.0069 Mean = 97.926 STD .-. 75 0.33 0.406 0.411 72.60 89.19 90.28 Mean = 0.382 STD = 0.0454 Mean = 84.025 STD = 80 0.332 0.372 0.363 73.03 81.77 79.80 Mean = 0.356 STD = 0.0210 Mean = 78.202 STD = Time(days)= 6 Calibration Curve: 'y=0.458 x - 0.0025" Table 40. 40C Raw Dissolution Data and Statistics (Day6) 60 1.51271 2.15410 4.74525 3.63610 3.28480 1.31609 4.03979 5.98349 3.15903 2.33465 1.51271 9.91068 4.58169 %Dissoiution Determination (4°C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 12 0.45 0.439 0.437 98.80 96.40 95.96 Mean = 0.442 STD = 0.00700 Mean = 97.052 STD = 1.52838 33 0.44 0.444 0.439 96.62 97.49 96.40 Mean = 0.441 STD = 0.0026 Mean = 96.834 STD = 0.57767 50 0.43 0.43 0.453 94.43 94.43 99.45 Mean = 0.438 STD = 0.0133 Mean = 96.106 STD = 2.89936 65 0.433 0.45 0.456 95.09 98.80 100.11 Mean = 0.446 STD = 0.0119 Mean = 97.999 STD = 2.60488 75 0.377 0.425 0.416 82.86 93.34 91.38 Mean = 0.406 STD = 0.0255 Mean = 89.192 STD = 5.57090 80 0.373 0.361 0.36 81.99 79.37 79.15 Mean = 0.365 STD = 0.0072 Mean = 80.167 STD = 1.57951 Time(days)= 9 Calibration Curve: 'y=0.458 x - 0.0025" Table 41. 400 Raw Dissolution Data and Statistics (Day9) %Dissoiution Determination (40C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 12 0.435 0.431 0.447 95.52 94.65 98.14 Mean = 0.438 STD = 0.00833 Mean = 96.106 STD = 1.81805 33 0.441 0.444 0.427 96.83 97.49 93.78 Mean = 0.437 STD = 0.0091 Mean = 96.033 STD = 1.98117 50 0.436 0.439 0.419 95.74 96.40 92.03 Mean = 0.431 STD = 0.0108 Mean = 94.723 STD = 2.35498 65 0.439 0.448 0.437 96.40 98.36 95.96 Mean = 0.441 STD = 0.0059 Mean = 96.907 STD = 1.27936 75 0.395 0.411 0.425 86.79 90.28 93.34 Mean = 0.410 STD = 0.0150 Mean = 90.138 STD = 3.27753 80 0.322 0.394 0.391 70.85 86.57 85.92 Mean = 0.369 STD = 0.0407 Mean = 81.114 STD = 8.89319 Time(days)= 12 Calibration Curve: 'y=0.458 x - 0.0025" Table 42. 40C Raw Dissolution Data and Statistics (Day12) 61 %Dissoiution Determination (40C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 50 0.431 0.435 0.442 94.65 95.52 97.05 Mean = 0.436 STD = 0.00557 Mean = 95.742 STD = 65 0.434 0.436 0.446 95.31 95.74 97.93 Mean = 0.439 STD = 0.0064 Mean = 96.325 STD = 75 0.35 0.403 0.422 76.97 88.54 92.69 Mean = 0.392 STD = 0.0373 Mean = 86.063 STD = 80 0.367 0.388 0.257 80.68 85.26 56.66 Mean = 0.337 STD = 0.0704 Mean = 74.199 STD = Time(days)= 15 Calibration Curve: 'y=0.458 x - 0.0025" Table 43. 400 Raw Dissolution Data and Statistics (Day15) %Dissoiution Determination (40C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 12 0.445 0.445 0.432 97.71 97.71 94.87 Mean = 0.441 STD = 0.00751 Mean = 96.761 STD = 33 0.444 0.442 0.45 97.49 97.05 98.80 Mean = 0.445 STD = 0.0042 Mean = 97.780 STD = 50 0.439 0.445 0.449 96.40 97.71 98.58 Mean = 0.444 STD = 0.0050 Mean = 97.562 STD = 65 0.435 0.442 0.424 95.52 97.05 93.12 Mean = 0.434 STD = 0.0091 Mean = 95.233 STD = 75 0.333 0.417 0.405 73.25 91.59 88.97 Mean = 0.385 STD = 0.0454 Mean = 84.607 STD = 80 0.244 0.318 0.283 53.82 69.98 62.34 Mean = 0.282 STD = 0.0370 Mean = 62.045 STD = Time(days)= 18 Calibration Curve: “'y=0.458 x - 0.0025” Table 44. 400 Raw Dissolution Data and Statistics (Day18) 62 1.21567 1 .40373 8.14716 15.36214 1 .63877 0.90902 1 .09896 1.98117 9.91949 8.08254 f. %Dissoiution Determination (4°C) ABS(AU) %Dissoiution %RH 111 #2 #3 #1 #2 #3 50 0.406 0.449 0.453 89.19 98.58 99.45 Mean = 0.436 STD = 0.02606 Mean = 95.742 STD = 5.68944 65 0.442 0.446 0.424 97.05 97.93 93.12 Mean = 0.437 STD = 0.0117 Mean = 96.033 STD = 2.55872 75 0.41 0.386 0.417 90.07 84.83 91.59 Mean = 0.404 STD = 0.0163 Mean = 88.828 STD = 3.54985 80 0.257 0.349 0.281 56.66 76.75 61.90 Mean = 0.296 STD = 0.0477 Mean = 65.102 STD = 10.41952 (2., is Time(days)= 21 Calibration Curve: 'y=0.458 x - 0.0025“ Table 45. 40C Raw Dissolution Data and Statistics (Day21) ,' u. %Dissoiution Determination (4°C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 50 0.43 0.429 0.421 94.43 94.21 92.47 Mean = 0.427 STD = 0.00493 Mean = 93.705 STD = 1.07705 65 0.438 0.444 0.409 96.18 97.49 89.85 Mean = 0.430 STD = 0.0187 Mean = 94.505 STD = 4.08672 75 0.402 0.407 0.347 88.32 89.41 76.31 Mean = 0.385 STD = 0.0333 Mean = 84.680 STD = 7.26892 80 0.356 0.379 0.291 78.28 83.30 64.08 _ Mean = 0.342 STD = 0.0456 Mean = 75.218 STD = 9.96504 Time(days)= 27 Calibration Curve: 'y=0.458 x - 0.0025“ Table 46. 4°C Raw Dissolution Data and Statistics (Day27) 63 %Dissoiution Determination (4°C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 12 0.44 0.441 0.442 96.62 96.83 97.05 Mean = 0.441 STD = 0.00100 Mean = 96.834 STD = 0.21834 33 0.43 0.445 0.439 94.43 97.71 96.40 Mean = 0.438 STD = 0.0075 Mean = 96.179 STD = 1.64844 50 0.432 0.441 0.437 94.87 96.83 95.96 Mean = 0.437 STD = 0.0045 Mean = 95.888 STD = 0.98455 65 0.434 0.438 0.445 95.31 96.18 97.71 Mean = 0.439 STD = 0.0056 Mean = 96.397 STD = 1.21567 75 0.381 0.362 0.402 83.73 79.59 88.32 Mean = 0.382 STD = 0.0200 Mean = 83.879 STD = 4.36863 80 0.319 0.299 0.362 70.20 65.83 79.59 Mean = 0.327 STD = 0.0322 Mean = 71.870 STD = 7.02885 Time(days)= 3 Calibration Curve: 'y=0.458 x - 0.0025" Table 47. 40C Raw Dissolution Data and Statistics (Day33) %Dissoiution Determination (4°C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 50 0.425 0.432 0.422 93.34 94.87 92.69 Mean = 0.426 STD = 0.00513 Mean = 93.632 STD = 1.12044 65 0.408 0.415 0.421 89.63 91 .16 92.47 Mean = 0.415 STD = 0.0065 Mean = 91.084 STD = 1.42061 75 0.329 0.401 0.399 72.38 88.10 87.66 Mean = 0.376 STD = 0.0410 Mean = 82.715 STD = 8.95285 80 0.3 0.351 0.354 66.05 77.18 77.84 Mean = 0.335 STD = 0.0303 Mean = 73.690 STD = 6.62620 Time(days)= 40 Calibration Curve: ‘y=0.458 x - 0.0025" Table 48. 400 Raw Dissolution Data and Statistics (Day40) %Dissoiution Determination (4°C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 50 0.406 0.427 0.425 89.19 93.78 93.34 Mean 2 0.419 STD = 0.01159 Mean = 92.103 STD = 65 0.42 0.419 0.41 92.25 92.03 90.07 Mean = 0.416 STD = 0.0055 Mean = 91.448 STD = 75 0.384 0.373 0.346 84.39 81.99 76.09 Mean = 0.368 STD = 0.0196 Mean = 80.822 STD = 80 0.245 0.265 0.21 54.04 58.41 46.40 Mean = 0.240 STD = 0.0278 Mean = 52.948 STD = Time(days)= 47 Calibration Curve: 'y=0.458 x - 0.0025" Table 49. 4°C Raw Dissolution Data and Statistics (Day47) %Dissoiution Determination (4°C) ABS(AU) %Dissoiution %RH #1 #2 #3 #1 #2 #3 50 0.438 0.423 0.438 96.18 92.90 96.18 Mean = 0.433 STD = 0.00866 Mean = 95.087 STD = 65 0.426 0.431 0.429 93.56 94.65 94.21 Mean = 0.429 STD = 0.0025 Mean = 94.141 STD = 75 0.397 0.359 0.408 87.23 78.93 89.63 Mean = 0.388 STD = 0.0257 Mean = 85.262 STD = 80 0.332 0.345 0.316 73.03 75.87 69.54 Mean = 0.331 STD = 0.0145 Mean = 72.817 STD = Time(days)= 54 Calibration Curve: "y=0.458 x - 0.0025" Table 50. 40C Raw Dissolution Data and Statistics (Day54) 65 2.53062 1 .20253 4.26929 6.07835 1 .89089 0.54948 5.61352 3.17158 References Adams, S. Dissolution Shelf Life of Hydroxygrogyl Methyl Cellulose Coated Aspirin Tablets at ICH Temperatures and Various Relative Humidities. MS. Thesis, Michigan State University. (1998) Banakar, U.V. Pharmaceutical Dissolution Testing, Marcel Dekker, Inc., NY. (1992) Eli Lilly and Company. Global Packaging and Development Laboratory Test Reports. (2000) Hanson, W.A. Handbook of Dissolution Testing, Aster Publishing Corporation, Eugene, Oregon. (1991) Taborsky-Urdinola, C.J., Gray, VA, and Grady, L.T. Am. J. Hosp. Pharm., 38:1322. (1981) The United States Pharmacopoeia 23. pp1791-1793, 1286. (1995) Yoon, 8. Shelf Life Estimation of USP 10 mgPrednisone Calibrator Tablet in Relation tflissolution. MS. Thesis, Michigan State University. (2000) Hygrodynamics Technical Bulletin No. 5. Creating ang Maintaining Humidities by Salt Solutions. (1967) 66 ‘ .91 ~ --. he . _ IIIIIIIIIIIIIIIIIIIIIIIIIIIIIII iHilllililiil[lilillilzllllllliljill