1. Handbook On Injectable Drugs Download

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. Part of the book series (AAPS, volume 3) Abstract A growing number of new therapeutic molecules are limited by low or erratic bioavailability due to poor water solubility. Because of the clinical demand for new and more efficacious anti-cancer, antiviral, and anti-infective drugs, many of these new drugs must be formulated for injection. Poor water solubility can be addressed by a range of formulation approaches such as pH manipulation, salt formation, and cosolvent and surfactant addition, or by more advanced techniques such as complexation, liposomal encapsulation, or nanosuspension. While remaining focused on drug solubility, issues such as buffering, tonicity, sterility, and drug ­product stability also must be considered when formulating injectable products. This chapter outlines a formulator’s approach toward development of an injectable drug product containing an active ingredient with poor solubility. Marketed injectable products, listings of GRAS excipients, and techniques for enhancing solubility are offered as case studies to assist in the formulation process.

Method. Prepare solutions of varying concentrations of PS80 (0, 2.5, 5, 10, and 20%) in citrate buffer with a pH of 4.3 and 8.4. Perform solubility study by placing 0.5 mL of each solution into vials with excess flavopiridol. Attach vials to rotator, place at 25°C, and rotate at 20 rpm for 6 days or until equilibrium solubility is achieved. (Note: The drug is stable for 2 months under these conditions). Filter samples through 0.45-μm syringe filter membrane and check final solution pH. Perform HPLC analysis of samples for potency (solubility) of flavopiridol.

Results. The solubility of flavopiridol in solution without surfactant was 1.37 mM and 0.055 mM at pH 4.3 and 8.4, respectively. The solubility of a drug in the micelle is influenced by the micellar partition coefficient and drug water solubility.

Increasing the concentration of PS80 resulted in a substantial linear increase in drug solubility. The increase was considerably greater (up to ∼27 mM at 20% PS80) at pH 4.3, where the majority of drug is ionized.

Solubilization of the ionized drug by PS80 is more critical than that of the unionized species for increasing the overall solubility due to the increased water solubility resulting from the increased solubility of drug in the micelles. Method Capsule 2Solubilization of a PWS Drug using a Combination of Cosolvent and Surfactant. Method. Determine the solubility of ENA in cosolvent–water solutions with concentrations up to 50% (w/v).

Determine the solubility of ENA in surfactant–water solutions with concentrations up to 20% (w/v). Determine the solubility of ENA in aqueous solutions containing up to 20% (w/v) cyclodextrins.

Based on the results from the above solubility studies, determine the solubility of ENA in nonaqueous solution containing different ratios of the best performing solubilizers: Cremophor EL and ethanol (0:100, 50:50, 60:40, 70:30, and 100:0% v/v). Select a number of ratios of Cremophor EL:ethanol from the previous stability study and assess formulation stability upon dilution with saline. Assess formulation physical and chemical stability at different storage conditions. Results. Aqueous solutions containing concentration of 50% ethanol, PEG400, PG, or glycerol have an ENA solubility of 0.531, 0.269, 0.181, and 0.038 mg/mL, respectively.

The solubility of ENA is increased to 0.395 and 0.410 mg/mL with 20% of Tween 80 and Cremophor EL, respectively. The solubility of ENA is increased to 0.169 and 0.190 mg/mL with 20% of HPβCD and HPγCD, respectively. Cremophor EL:ethanol ratios of 0:100, 50:50, 60:40, 70:30, and 100:0 increased the solubility of ENA to 1.25, 3.90, 4.54, 5.42, and 6.65, respectively. Of all the ratios screened, only a combination of 70% Cremophor EL and 30% ethanol containing 4 mg/mL of ENA did not precipitate upon dilution (5- to 20-fold) with saline. This formulation is physically and chemically stable for over 4 months at either 5°C or room temperature. Method Capsule 3Solubilization Using a Combination of Complexation Agent and Cosolvent. Results.

An exponential increase in the solubility of fluasterone is observed in a cosolvent and water system with increasing ethanol concentration. Using HPβCD in an aqueous solution yields a linear increase in drug solubility corresponding with increasing HPβCD concentration. As ethanol concentration increases from 0.2 to 25.06% in the presence of HPβCD, the polarity of the solvent decreases. The result is reduced drug complexation within the HPβCD cavity and a decrease in the drug solubility over this range, with a minimum at 25.06%. At high ethanol concentrations (25.06–75%), the solubility increases due to the increase in the concentration of free drug and ternary complex. With the ethanol concentration held constant (25.06%), there is a linear increase in drug solubility with increasing amounts of HPβCD. Method Capsule 4Preparation of a Submicronized Injectable Emulsion Formulation.

Method. The formulation is composed of 0.5% (w/w) diazepam, 20% oil, 1.2% phospholipids, 2% poloxamer, 2.25% glycerin, 0.02% α-tocopherol, 0.2% methyl and 0.075% butyl p-hydroxybenzoic acid, and water for injection to 100 g. Perform preparation and processing with nitrogen atmosphere and sterile conditions. Add poloxamer, glycerin, and preservatives to the aqueous phase and dissolve. Dissolve phospholipids and diazepam in the oil phase containing α-tocopherol. Filter both phases, and heat separately to 70°C while mixing with a magnetic stirrer. Increase the temperature to 85°C for the emulsification step using the high-shear mixer.

Once the emulsion is formed, cool rapidly. A reduced droplet size is achieved using the two-stage Gaulin homogenizer. Adjust pH to the desired level with sodium hydroxide and filter the emulsion. Method. Use the double-emulsion process to produce breviscapine MVLs.

Prepare a lipid mixture in 1 mL chloroform–diethyl ether with 40 mg phosphatidycholine, 8 mg phosphatidylglycerol, 40 mg cholesterol, and triolein or ­tricaprylin at a 5.75:1 molar ratio of phosphatidycholine to total triglyceride content. Prepare an aqueous solution containing 40 mg/mL of breviscapine, 4% w/v sucrose in 50 mM arginine buffer pH 7. Emulsify the lipid and aqueous solutions to make a W/O emulsion at 10,000 rpm for 8 min with the mixer. Prepare the second aqueous solution with 40 mM L-Lysine and 3.4% glucose and emulsify with the W/O emulsion to form a W/O/W emulsion. Transfer to an Erlenmeyer flask and remove the chloroform–diethyl ether by nitrogen flushing the liquid surface at 30°C.

Centrifuge at 600 g for 5 min to remove free breviscapine from the MVLs and resuspend in a buffered saline solution. Method. Mix CBZ (final emulsion concentration of 2 mg/mL) with castor oil or a 1:1 mixture of castor oil:MCT (w/w) and prepare the lipophilic emulsifier ­(soybean lecithin or polyoxyl 35 castor oil at 6% w/w) by dissolving it in a 50:50 mixture of acetone:ethanol (v/v). Make the oil phase by adding the prepared emulsifier to the drug:oil dispersion. Prepare the aqueous phase by dissolving 4% (w/w) PS80 and 2.5% (w/v) glycerol in water. While stirring (moderate speed) with a magnetic stirrer, slowly add the oil phase to the aqueous phase to form the nanoemulsion.

Handbook On Injectable Drugs Download

Remove solvent and water by reducing the pressure, adjust pH to 7.0 with 0.1 M sodium hydroxide, and store the emulsion at 5°C. Results.

The emulsion droplets are spherically shaped, have an amorphous core, and range in size from 100 to 250 nm. The resulting optimized nanoemulsion formulation demonstrates 3 months ­stability based on droplet size, polydispersity, zeta potential, and drug content data.

The drug nanoemulsion meets requirements for IV administration and will be tested for in vivo evaluation. Method Capsule 7Preparation of an IV Nanosuspension Formulation for Reduced Irritation and Phlebitis upon Injection. Method. Perform all the following steps under reduced lighting conditions to protect the light-sensitive drug. Jet mill the coarse powder of nimodipine to produce a microparticulate powder. Disperse with a magnetic stirrer 0.5% (w/v) the milled powder in an aqueous solution composed of 0.6% (w/v) poloxamer 188, 0.4% (w/v) sodium cholic acid, and 4.0% (w/v) mannitol.

Perform pre-milling using the high-pressure homogenizer (maintain sample temperature at 25–30°C) by starting with the settings at 200 bar with two cycles then increasing to 500 bar with five cycles. Follow the pre-milling step with 15–20 cycles at 1,500 bar to produce the nanosuspension. Lyophilize the nanosuspension by drying for 15 hr at −15°C (below 200 mTorr), with a secondary step of 3 hr at −5°C, and a final step of 2 hr at 20°C.

Sterilize by gamma irradiation for 6 hr with an absorbed dose of 12 kGy.

Basic Facts Assisting the Pharmacist and Basic Facts Question Answer Drug names consist of what three names? Generic, Brand, and Chemical National Drug Code can be found in which book? Red Book or Blue Book What is the expiration date? It is based on shelf life of the drug United States Pharmacopoeia USP, contains official drug standards and is a required reference source is all licensed pharmacy settings. Temington's Pharmaceutical Sciences reference book used to look up formulas Handbook on Injectable Drugs Parenteral Product Reference Materials Guide to Parenteral Admixtures Parenteral Product Reference Materials Facts and Comparisons updated monthly and has information concering new drugs and contains information of drug to drug interactions.

American Drug Index Provides all the following: Brand to Generic cross referencing, available medication dosage forms, and manufacturer name, address and phone number Authority to prescribe is determined at what level? State The state determines the extent of a practitioner's prescription authority based on what? The Scope of his or her practice. Who is responsible for infection control?

The Center for Disease Control This is the process of preventing the transmissions of blood-borne pathogens. Universal Precautions Physicians MD, DO Podiatrists DPM Dentists DDS, DDM Optometrists OD Veterinarians DVM Physician assistants PA Which postal service CANNOT be used to send controlled substances to patients? US Postal Service Which postal services can be used to send controlled substances to patients?

FedEx or UPS Federal law mandates that only who may take a verbal prescription orders from a physician? Pharmacist Which postal services can be used to send controlled substances to patients? FedEx or UPS Federal law mandates that only who may take a verbal prescription orders from a physician? Pharmacist What are the contents of prescriptions? Patient information, date, name of product, strength, dosage form, quantity, sig., label directions, refills, prescriber information Who can recieve refill requests from patients?

Anyone in the pharmacy What methods are used to recieve electronic transmission of prescriptions? Fax, modem, computer link If the patient asks for generic, what number do you put in the computer? Number 2 If the doctor writes DAW, you choose what number? Number 1 If the doctor writes for a generic, what number do you choose? Number 0 Which book contains two letter codes assigned to drugs for therapeutic equivalence and is an appropriate reference for drug related information? The orange book What does it mean to be pharmaceutically elegant?

Labels on bottles are neat, correct size bottles are used The complete or nearly complete deprivation of moisture of or water not chemically combined. Desiccation The process of separating a solid from a fluid by pouring the mixture on a cloth which will permit the fluid to pass through, but will retain the solid. Colation The process tat involves a change of state - from liquid to vapor and back to a liquid Distillation The grinding of tablets into a fine powder in a porcelain mortar. Trituration The process of separating liquids from solids with the purpose of obtaining optically Filtration Used for extemporaneous compounding.

Size vary from 5 (the smallest) to 000, the largest. Gelatin Capsules The process of producing a smooth dispersion of a drug with a spatula. Levigation Is defined between 15-30 degress centigrade and 59-86 degrees Fahrenheit Controlled Room Temperature Defined as between 2 to 8 degrees C or 46 to 59 degrees F. Refridgeration The grinding of tablets into a fine powder in a porcelain mortar. Trituration The ability for medication to maintain chemical and physical integrity over time.

Stability Used for extemporaneous compounding. Size vary from 5 (the smallest) to 000, the largest.

Gelatin Capsules Is defined between 15-30 degress centigrade and 59-86 degrees Fahrenheit Controlled Room Temperature Defined as between 2 to 8 degrees C or 46 to 59 degrees F. Refridgeration Added to suspensions to thicken the suspending medium and the sedimentation rate. Suspending or thickening agents The ability for medication to maintain chemical and physical integrity over time. Stability The process of distilling volatile solids.