Adventures in Aseptic Admixtures: A CRASH Course

A D V E N T U R E S w i t h A S E P T I C A D M I X T U R E S:: 

A D V E N T U R E S w i t h A S E P T I C A D M I X T U R E S: Nishant B. Thakar Pharm D. Candidate University of Illinois at Chicago College of Pharmacy F A L L 2 0 1 1 A C O U R S E

C A U T I O N: 

C A U T I O N RATED: PARENTERAL GUIDANCE SUGGESTED EXCESSIVE DRUG CONTENT, VIOLENCE, SUGGESTIVE SUGGESTIONS, MILD PHARMACEUTICAL LANGUAGE, ESTER AND BETA-LACTAM CLEAVAGE

BASIC IDEA OF ASEPTIC ADMIXTURES: 

BASIC IDEA OF ASEPTIC ADMIXTURES You are taking contents of an SVP and placing it into a LVP With the aseptic admixture problems, you are determining to see if there it is compatible (no reactions/interactions) or incompatible (reactions/interactions)

S E V E N S I M P L E R U L E S O F A S E P T I C A D M I X T U R E S: 

S E V E N S I M P L E R U L E S O F A S E P T I C A D M I X T U R E S

R U L E 1 : W E A K A C I D S: 

R U L E 1 : W E A K A C I D S ALL Na + and K + salts are weak acids ( NO EXCEPTIONS ) NaOH + drug-H  H 2 O + drug - Na + KOH + drug-H  H 2 O + drug - K + EXAMPLES: Phenytoin Na Amoxicillin Na PenicillinV K Diclofenac K

R U L E 2 : W E A K B A S E S: 

R U L E 2 : W E A K B A S E S ALL HCl, SO 4 = , PO 4 ≡ salts are weak bases ( NO EXCEPTIONS ) drug-OH + HCl  H 2 O + drug - H + Cl - EXAMPLES: Morphine SO 4 Hydromorphone HCl Codeine PO 4 Verapamil HCl

R U L E 3 A : A C I D I C p H: 

R U L E 3 A : A C I D I C p H Weak acids in acidic pH will yield a poorly soluble FREE ACID. Na + PCN – + H + Cl – (acid)  Na + + Cl – + PCN 0 ↓ (free acid)

R U L E 3 B : B A S I C p H: 

R U L E 3 B : B A S I C p H Weak bases in basic pH will yield a poorly soluble FREE BASE. Verapamil H + Cl – + Na + OH – (base)  Na + + Cl – + H 2 O + Verapamil 0 ↓ (free base)

R U L E 4 : I O N P A I R: 

R U L E 4 : I O N P A I R W.A. + W.B.  ion pair (ppt) Na + PB - + RanitidineH + Cl -  PRODUCTS: NaCl (dissociates in solution) RanitidineH + PB - (ion pair) Most ion pairs are insoluble . You would need to check a reference like Trissel’s or King’s

R U L E 4 : I O N P A I R: 

R U L E 4 : I O N P A I R You can make a chart like this to find the ion pair. Na + PB – RanitidineH + Cl – C A T I O N S A N I O N S

R U L E 5 : L V P s: 

R U L E 5 : L V P s These are the large volume solutions that you will ultimately put the contents of the small volume parenterals into. THREE FLAVORS: Acidic pH Basic pH Neutral pH

R U L E 5 : L V P s: 

R U L E 5 : L V P s NEUTRAL pH: Ringer’s: (NaCl, KCl, CaCl 2 ) Ringer’s Lactate: (NaCl, KCl, CaCl 2 , Na Lactate) D 2.5 W and D 5 W (slightly acidic  neutral) NaCl (0.45%, 0.9%) ACIDIC pH: Dextrose solutions > 10% Solutions with pH < 6 BASIC pH: > 5% NaHCO 3 LVPs Solutions with pH > 8 Na Heparin in THERAPEUTIC CONCENTRATIONS in LVP

R U L E 5 : L V P s (N a H e p a r i n): 

R U L E 5 : L V P s (N a H e p a r i n) Na Heparin is a weak acid by itself. ( REMEMBER Rule #1) However, the negative charge on the heparin is diffused throughout a very large mass. Because of this, the negative charge is not very strong, compared to the strength of the positive charge of Na + . The strong positive point charge of Na + does a much better job attracting the OH components from H 2 O, than heparin’s ability to attract H + from H 2 O. Hence, this solution, in therapeutic concentrations , is BASIC.

R U L E 6 : S P E C I A L D R U G S: 

R U L E 6 : S P E C I A L D R U G S There are certain drugs that have things you have to watch out for. 6 A: Penicillins Ampicillin 6 B: Ester Drugs 6 C: Tetracyclines/Fluoroquinolones 6 D: Phenytoin

R U L E 6 : P E N I C I L L I N S: 

R U L E 6 : P E N I C I L L I N S Antibiotics that contain β-lactam ring (a cyclic amide)

R U L E 6 A : P E N I C I L L I N S: 

R U L E 6 A : P E N I C I L L I N S Because of this β-lactam ring, they are prone to hydrolysis by EITHER acidic pH or basic pH

R U L E 6 A : P E N I C I L L I N S: 

R U L E 6 A : P E N I C I L L I N S A M P I C I L L I N D E X T R O S E N a C l

R U L E 6 B : E S T E R S: 

R U L E 6 B : E S T E R S Certain poorly soluble drugs are esterified and formed into a salt in order to remain in solution. EXAMPLES: hydrocortisone, chloramphenicol

R U L E 6 B: E S T E R S: 

R U L E 6 B : E S T E R S The ester bond is prone to hydrolysis by either a BASIC environment OR an ACIDIC environment.

R U L E 6 C : TETRACYCLINES/ FLUOROQUINOLONES: 

R U L E 6 C : TETRACYCLINES/ FLUOROQUINOLONES Tetracyclines and fluoroquinolones bind to divalent AND trivalent cations . Tetracyclines: Doxy cycline , Mino cycline Fluoroquinolones: Cipro floxacin , Levo floxacin , Moxi floxacin , etc. Ca Fe Mg Al ++ ++ ++ +++

R U L E 6 D : P H E N Y T O I N: 

R U L E 6 D : P H E N Y T O I N Phenytoin is poorly water soluble Hence, it is ONLY soluble in NS, but only for 30 minutes. 0 . 9 % N a C l C A U T I O N S T A B L E F O R 3 0 M I N U T E S

R U L E 7 : S O L U B I L I T Y: 

R U L E 7 : S O L U B I L I T Y

SUMMARY OF SEVEN RULES: 

SUMMARY OF SEVEN RULES 1) ALL Na + , K + salts of drugs are WEAK ACIDS 2) ALL HCl, SO 4 = , PO 4 ≡ salts of drugs are WEAK BASES 3 A) Weak acid drugs in acidic pH  FREE ACID ↓ 3 B) Weak base drugs in basic pH  FREE BASE ↓ 4) W A + W B  ION PAIR (most likely insoluble) 5) LVPs Acidic: Dextrose > 10%, acidic pH (< 5) Basic: NaHCO3, NaHep in THERAPEUTIC conc in LVP, basic pH ( > 8) Neutral: Ringers, RL, Dextrose 2.5% – 5%, NaCl 6) SPECIAL CASES: Penicillins: β-lactam ring prone to acid/base hydrolysis Ampicillin: ONLY compatible in NaCl Esterified drugs: ester bond prone to acid/base hydrolysis Tetracycline/Fluoroquinolones: Chelate with divalent and trivalent cations Phenytoin: ONLY compatible for NaCl for 30 minutes 7) SOLUBILITY CHART

E X A M P L E P R O B L E M: 

E X A M P L E P R O B L E M

PowerPoint Presentation: 

LVP  SVP ↓ RL w/ 20,000 Units of Na Heparin D 50 W 0.9% NaCl w/ 5% NaHCO 3 D 5 W w/ Ampicillin Na Hydrocortisone –Succinate Na INACTIVES: contains PO 4 ≡ buffers, benzoyl alcohol, SWFI Doxycycline HCl INACTIVES: ascorbic acid Morphine 2 SO 4 INACTIVES: ascorbic acid, phenol MgSO 4 W A W B N ACIDIC pH (TCN) (ESTER) W B C I BASIC pH NEUTRAL pH BASIC pH Ca ++ I 1) Base hydrolysis of ester bond 2) Ca 3 (PO 4 ) 2 PPT 1) Acid hydrolysis of ester bond Base hydrolysis of ester bond I C C I I I I I I I I I I 2) F R E E A C I D ALREADY INCOMPATIBLE 1) TCN-Chelation w/ Ca ++ 2) F R E E B A S E F R E E B A S E I O N P A I R (DoxyH + Amp - ) 3) ION PAIR (DoxyH + Hep - ) W A W A 2) CaSO 4 PPT 1) ION PAIR (MoprhineH + Hep - ) F R E E B A S E I O N P A I R (MorphineH + Amp - ) CaSO 4 PPT MgCO 3 PPT

F I N A L E X A M: 

F I N A L E X A M Final Exam contains 5 0 points on aseptic admixtures. SVPs will contain preservatives LVPs may already incompatible You have a lot more things to watch out for. Please e-mail/see us if there are any questions.

Q U E S T I O N S ?: 

Q U E S T I O N S ? Nishant B. Thakar, Pharm D. Candidate University of Illinois at Chicago College of Pharmacy nthaka3@uic.edu / nbthakar@hotmail.com