This action might not be possible to undo. Are you sure you want to continue?
Chemical Principles Applicable to Formulation Developments
Shaukat Ali, Ph.D. Technical Service Manager Ledgewood, NJ 07852
ExcipientFest San Juan, Puerto Rico April 23, 2009
Chemistry 101 for Non-Chemists Part II
Chemical Principles Applicable to Formulation Developments (primarily Solid Oral Dosage Forms): Formulation development requires a balance between physical and chemical properties. This session will continue to elaborate on basic chemical principles that need to be taken into consideration to achieve what is normally referred to in the industry as a robust formulation. Concepts such as excipient selection (binders and disintegrants), possible API and excipient interactions, and how to achieve the desired physical and bioequivalent results will be addressed. A basic explanation on pharmaceutical coatings, their chemistry and corresponding functionality will also be covered.
The Drug Formulation Balance
Highly Regulated Environment
Safety & Efficacy
Process / Operations: Weighing Sizing Blending / Granulation Compression / Encapsulation Coating Packaging FORMULATION IS A BALANCING ACT! No one right answer .it depends (balancing tradeoffs)! INPUT + Formulation & Processing = Physical Chemical Functional OUTPUT .Excipient Role API Excipients: a) Fillers b) Binders c) Disintegrants d) Lubricants e) Glidants f) Solubilizers Delivery Form: Physical Tablet Characteristics: a) Weight (running weight variability) b) Dimensions c) Hardness (breaking strength) d) Friability e) Disintegration Time Manuf.
or JPE) .Excipients Characteristics Chemically inert carriers in the formulation Present in significantly large quantity in a dosage Properties dependent upon formulation or delivery systems Enhance the functions to the dosages Requires less stringent qualification criteria Safety and toxicological profiles well understood Robust methods to characterize them Meet Pharmacopeial specifications (USP. EP.
Type of Excipients Fillers Compression aids Binders Disintegrants Lubricants Glidants Preservatives Suspending agents Opacifiers Sweeteners Flavors Film formers/coatings Pigments Print Inks IPEC brings the transparency between suppliers and drug manufacturers .
binders. sustained release or enteric release Moisture barrier Influence dissolution and release profile Influence stability of the dosage form .Role in Pharmaceutical Dosage Tablets and Pellets Fillers. and solubilizers Functional coatings Instant release. glidants. superdisintegrants.
tapped.Characterization Particle Size distribution Porosity Moisture level Surface area Flowability Density (bulk. true) Viscosity Degree of substitution Molecular weight Peroxides Others .
ring opening Hydrogen bonding Aldehyde-amine.and disaccharides Basic pH Silanol Amine. carbohydrates Bases Oxygen Oxygen Metals Amine-aldehyde. Schiff base Salt formation Oxidation Dimerization Complexation . amineacetal Hydrolysis.API-Excipient Interactions Functional group R-NH2 (amine) R-COOR’ (esters. lactones) R-C(O)R (carbonyl) R-C(O)H (aldehyde) R-CO2H (carboxylic acid) RCH2OH (alcohol) RCH2SH (Sulfhydryl) PhOH (Phenol) Incompatibility Possible Interaction Mono.
Oxazolam/MCC. dye excipients. metal ions Amines with reducing sugars. alkaline microenvironment Amines react with aldehydes Undesirable pH conditions Enzymetic condition. Ibuprofen or Aspirin/Mg stearate Aspirin/excipients. Lansoprazole/excipients Ceronapril/Dicalcium Phosphate. B12 Benzocain/Polyvinylacetate phthalate. pH controlled Maillard reaction Schiff base formation Drug-buffer interaction Trans-esterification . Type of reaction Condition Acid/base Complexation Capable of donating protons and hydroxyl ions Capable of interacting each other through H-bondings or ionization Example Indomethacin/NaHCO3. Raloxifen/PVP/crospovidone Ceronapril/lactose. Diclofenac sodium/polymethacrylic acid copolymer. Isoniazid/lactose. Bisulfite.API-Excipient Interactions…contd. Fluoxetine HCl/lactose Gelatin capsules/PEG400 linkage with aldehyde Epinephrine/sod. Citric acid or tartaric acid/NaHCO3 CaCO3/tetracycline. isomerization of Vit. Norfloxacin/Mg stearate amide cross- Hydrolysis Oxidation Changes in the microenvironment Peroxides.
predictive tools and analytical methods Formulation dosages or delivery system Drug-excipient compatibility by selecting the “smart excipients” in the prototype formulation to alleviate interactions with API Important to assess certain risks in early stage of formulation development to avoid any surprises .Excipient Selection Criteria Prior knowledge on the function of excipients Expert systems.
Processing and Characterization No Formulation Optimization Stability Evaluation No QbD Scale up and Validation No Manufacturing .Process Flow Chart API Excipients Yes Prototype Formulation.
Factors Affecting the Formulation Stability Drug & Excipient Formulation Environment Chemical structure Impurity profile Physical form Moisture content Particle size Surface area Morphology Crystal defects Drug : Excipient ratio Processing method Physical mixing/ milling or granulation Powder mixing and packing Probability of chemical interaction with API Temperature Relative humidity Packaging Light Oxygen .
but in wet granulations. alkaline agents retards API degradation due to presence of moisture Stabilization by salt formation .5 mg) tablets showed a significant oxidative decomposition Moexipril Stabilizes NCarboxylalkyl dipeptide via aminolysis at pH < 4.Stabilization of Formulation Dosages Instability and Solutions Captopril Drug : Excipient ratio Study showed decomposition in the present of Mg stearate High strength (100 mg) tablets with Mg stearate are stable Low strength (12.5 and ester hydrolysis at pH >10 Excipients are incompatible in dry state.
no adsorption Ibuprofen Forms eutectic in presence of Mg stearate which vaporizes Film coating of tablets eliminates this problem .Stabilization of Formulation…contd. Dosages Instability and Solutions Enalapril MCC incompatible with API due to adsorption and dissociation of amine maleate of drug Ca-Phosphate compatible with API.
Stabilization of Formulation Basic Requirements and Solutions Altering the properties of solid drug Minimizing the level of moisture in formulation SOLUTIONS Increasing melting point Choosing a nonhygroscopic form (crystal or salt form) Reducing solubility by choosing a less soluble salt Micellar inclusion Complexation Engineering of the particles (shape) SOLUTIONS Choice of excipients Co-solvents Manufacturing conditions Storage conditions Packaging .
or buffer salts Incorporating complexation agents to inactivate trace metal ions Displacing oxygen with nitrogen or argon Incorporating antioxidants SOLUTIONS Coating with polymers/ microencapsulation Multi-layer particles in capsule/tablet Tablet in a tablet or capsule . and water SOLUTIONS Adjusting the pH by using acids. bases.Stabilization of Formulation…contd. Basic Requirements and Solutions Changing the microenvironment in formulation Minimizing contact between API & Excipients.
Eur.g. etc. ODT) Gonnissen et la. 67.) Mannitol is low hygroscopic of all three (e. Pharm. %(w/w) 10 8 6 4 2 0 Maltodextrin Lactose Mannitol 32 52 65 75 85 Relative Humidity (% w/w) Maltodextrin poses a compressibility challenge Lactose is often used in the formulations (eg. Zyrtec OTC. 220-226 . Biopharm. J. 2007..Excipient and API Incompatibility Excipients under different %RH Moisture Uptake.
10. Phos. HPMC Lactose Mg PVP K-30 Primojel Stearate Excipient Wyttenbach et al... Pharm Dev and Tech.Formulation Dosage Stability Aspirin: Impact of moisture absorption Moisture absorption decreases in the order: Dicalcium phosphate > MCC > Lactose Aspirin degradation @ Varied %RH 100 80 60 40 20 0 10 %RH 75 %RH DCP has more impact on instability of drug due to increase in internal pH resulting from moisture uptake D e g r a d a t io n . 499. 2005. % Avicel Calc. .
Drug Stability. 3rd.chemical properties of API by increasing the molecular mobility that leads to phase separation and crystallization 0 15 35 45 55 65 70 Relative Humidity (%) Stubberud et al.Formulation Dosage Stability…contd. 134. Ed. 79-88. J.. 50 80 90 Relative Humidity (%) Cartensen and Rhodes. 134. 1996.. . 70 Pharm. Indomethacin: Impact of moisture absorption 180 150 PVP K-25 5% Moisture Uptake 30% Tg (oC) 120 90 60 30 0 Water acts as a plasticizer and lower Tg of the excipient and alters the physico. Pharm.. 10 8 kobs x104 6 4 2 IND decomposition Rate constant is correlated with amount of moisture IND crystallizes under high %RH 0 Stubberud et al. J. Int. 79-88. Int.. 1996.
04 0 CBZ CBZ-K30 (1:5) CBZ-K-30CBZ-K-30Gelucire 44/14 TPGS (1:4:1) (1:4:1) CBZ/Excipient Dissolution rate: PVP K-30 > Vit.12 0.16 0. E-TPGS > Gellucire 44/14 Sethia and Sequillante. Pharm.2 Intrinsic Dissolution rate (mg/min/cm2) 0. 2004. Int. J.Influence of Excipients on the Dissolution of an API Carbamazepine (CBZ) and PVP w/wo Solubilizers 0.08 0. 1-10 . 272.
2007.Influence of Excipients on the Dissolution of an API CBZ in Different Dissolution Media 150 min H2O H2O PEG 500 μm CBZ HPMC Rate of CBZ dissolution: Water > PEG > HPMC Faster dissolution of CBZ Dihydrate was due to increased surface area Tian et al. J.. Pharm. 96.. Sci. 584-594 .
Excipient-API Incompatibility Excipient’s Particle size on Aspirin Stability Aspirin degradation in presence of microcrystalline and microfine-cellulose (55°C/75% RH) Stability decreased with increasing amount of cellulose presumably due to the catalytic effect Ahlneck et al (1988) .
4 0 Kollicoat Protect:Kaolin:Talc (60:25:15) Kollicoat Protect:Kaolin:Talc (40:40:20) PVA based Com petitor Product Coated Aspirin Tablets PVA-co-PEG is an effective moisture barrier polymer .8 0. API 100 mg. 301. % 0. Coating level 3.Dosages Stability – Functional Coating Aspirin Stability (6 months) Tablet wt.5 mg.2 25 oC/60%RH Salicylic acid.7 wt% 1.
Effect of Binders on Dissolution of API Ibuprofen Dissolution properties dependent on the binder selection Possible interaction of Ibuprofen with DCP .
% 40 20 0 Crospovidone Croscarm ellose Sodium Carboxym ethystarch L-HPC Superdisintegrants Crospovidone ≥ Croscarmellose Sodium > Carboxymethylstarch > L-HPC .Superdisintegrants in Performance of Phenacetin Tablets Disintegrant @5% 100 80 60 Dissolution @15 min Dissolution.
Functional coating with Polyvinylacetate dispersion 30% Effects of pore formers on Theophylline release 30% PVP K-90 30% PVP K-90 FASTER Dissolution Far more porous 30% PVA-co-PEG 15% PVP K-90 30% PVA-co-PEG 15% PVA-co-PEG Less porous 30% PVP K-30 no pore former 30% PVP K-30 Theophylline release from the pellets coated with Kollicoat SR 30D with and without pore-formers Far less porous SLOWER Dissolution .
Hr 3 4 5 Achieve a similar release (0-2 Hr) from both coatings Provide more flexibility Easy manufacturing .Coating Excipients in the Performance of Products Tablets versus Pellets Enteric Copolymer Methylacrylic acid-ethyl acrylate co-polymer 100 Aspirin Tablet Enteric coated tablets 80 Released. % 60 40 20 Ascorbic Acid Pellets Enteric Effect Multi-layered pellets Sustained release Polyvinylacetate 30% 0 0 1 2 Time.
Generic Rx Years .Drug Approval Process Brand Rx vs.
..Bioequivalency of a Drug Product Definition Pharmaceutical Equivalent Products Brand Rx Same Active Possible Differences Drug particle size. Excipients Manufacturing process Equipments Site of manufacturing Batch size …. Flowability. Generic Rx Therapeutic Equivalence (Same dissolution spec. PK profile) .
Determine the Bioequivalency Comparison of PK Profiles in Plasma Generic Rx Concentration Cmax Brand Rx The AUC and Cmax of the generic Rx must meet 80% .125% of the brand Rx in order to be deemed BE AUC Tmax Time Food and Drug Administration Web site. .
Generic Rx FDA Requirements Pharmacokinetic (PK) Reference Range 80% 100% 125% Product A Bioequivalent Brand Rx (Reference Drug) Product A is BE to Brand Rx Product B is not BE Product B Not Bioequivalent Food and Drug Administration Web site .Bioequivalency of Brand Rx vs.
Achieving the Bioequivalency Dissolution profiles of Generic Rx to Brand Rx 120 100 Brand Rx Generic Rx Released. % 80 60 40 20 0 0 4 8 12 16 20 24 Time. hr Dissolution profiles of brand Rx and generic Rx very close .
Achieving the Bioequivalency PK profiles of Brand Rx and Generic Rx SRx-501 (Levodopa-Carbidopa XR) SRx-502 meets bioequivalence criteria of Topamax for both Cmax and AUC The fluctuation index is identical in both Brand Rx and Generic Rx The PK data of SRx-502 supports approval based on bioequivalence Source: Spherics .
1991. Pharm.. J. 175-178 .Efficacy and Bioavailability-PK Profiles Effects of excipients on highly and poorly permeable drugs Highly Permeable Drug Water Sorbitol Theophylline serum concentration profiles About 10 grams of sorbitol had no (minimal) effect on bioavailability (Cmax and AUC) of theophylline Fassihi et al. Int. 72.
.3 grams of mannitol in a chewable tablet reduced bioavailability of cimetidine compared to a tablet containing the same amount of sucrose Adkin et al. J.Efficacy and Bioavailability-PK Profiles…contd. Sci. Pharm. Effects of excipients on highly and poorly permeable drugs Poorly Permeable Drug Sucrose solution Chewable Sucrose tablet Mannitol Solution Chewable mannitol tablet Cimetidine serum concentration profile 2. 84. 1995. 1405-1409 .
Bioavailability of a Class III Drug PK profiles of Ranitidine Ranitidine (poorly permeable drug) 500 LnCmax 44%-54% Plasma Conc. (ng/mL) 400 300 200 100 0 Sucrose Sorbitol LnAUCi 53%-62% Ranitidine: 150 mg Sucrose: 5 g Sorbitol: 5 g 0 2 4 6 8 10 12 Time (hours) Sucrose metabolizes to glucose and fructose. AAPS 2000 . and both show complete absorption Hussain.. A.
storage and packaging conditions Safety and toxicological profiles A comprehensive knowledge of APIs and Excipients is required to minimize any late stage development surprises!! . method validation and testing Product manufacturing processes and robustness Stability.Concluding Remarks Selection of the API Selection of the excipients and compatibility in formulation Development of analytical methods.
Success in Formulation Design Perseverance… Thomas Edison Many of life's failures are people who did not realize how close they were to success when they gave up. .
This action might not be possible to undo. Are you sure you want to continue?
We've moved you to where you read on your other device.
Get the full title to continue reading from where you left off, or restart the preview.