Stability of micronutrients in PN – what is known and what can be claimed ? Prof. Mike.Allwood Pharmacy Consultant
Pharmaceutical interactions 1. Physical incompatibility = precipitation Caused by: Certain trace elements forming Insoluble salts to form sub-visible particles
2. Chemical instability = loss of activity Caused by chemical degradation of particular vitamins Micro-precipitate detection
Electron-dispersal X ray analysis linked to Electron-microscopy (EDX-SEM) Method - Analyse the filter surface after filtration of entire PN mixture Advantages: 1.Identifies each element present in precipitate 2.High sensitivity
Allwood,M.C.&Greenwood,M(1992)Pharm.Weekblad:14;321-5 Scanning Electron Microscope
(SEM)
with
X Ray Energy - Dispersive Spectroscope
(EDX) Sample Preparation
In L F Cabinet
1. Filter entire content
0.45 mm Filter SEM -EDX Preparation
Sample Filter
0.5 cm square
Gold Coat Carbon Coat
SEM EDX EDX Analysis
Spectrometer
X rays For Elemental Identification (A.W > 12)
Compatibility of Trace elements
Some micro-precipitates can be formed during storage in complete PN mixtures:
Iron phosphate – with Synthamin Avoid by using: a. Adding ascorbic acid ( or multivitamins) b. Use EF and organic phosphate
Allwood et al. (1998) Clin.Nutrit.17:223-6 Copper sulphide
Copper sulphide – from hydrogen sulphide – a degradation product of cysteine/cystine, as found in
eg.Vamin - limits shelf lives to 8 days ( Vamin 9) or 16 days ( Vamin 14;18)
selenium
Selenate reduction to selenium ( insoluble) – caused by low pH + high concentrations of ascorbic acid ( not a risk in practice)
In practice, rarely observed
Ganther,H.E.(1990).JPEN:14;223 Chemical stability of PN mixtures
Stable constituents ( ie. Less than 10% degradation within nlt 28 days): Amino acids ( exception- cysteine/cystine?) Glucose Fat Electrolytes and trace elements Most vitamins Vitamins - chemical stability
Critical concern -
. Chemical degradation during storage- Oxidation of ascorbic acid
Vitamin C degradation Pathway
Ascorbic Acid
O2
Dehydro-ascorbic Acid
H2O
Diketo-Gulonic acid
Oxalic Acid Degradation of ascorbic acid
Ascorbic acid degrades by oxidation = * Direct reaction with oxygen * Reaction catalysed by copper
Degradation products: Stage 1: +oxygen – fast reaction Dehydroascorbic acid ( biologically active) Stage 2: -hydrolysis- moderately fast reaction Diketo-gulonic acid ( biologically inactive) Stage 3:-further hydrolysis – slower reaction Oxalic acid Degradation after mixing
How much ascorbic acid degrades in PN ? Total amount lost depends on oxygen load – from: Oxygen in ingredients ( glucose, saline, ,electrolytes) Aeration of solutions during filling process Air in bag after sealing oxygen transmission across bag walls
How quickly does ascorbic acid degrade ? Degradation of Ascorbic Acid in EVA bags
100
90
80
70
60
50 40
30
20
% Ascorbic% Acid remaining 10
0 0 1 2 3 4 5 6 7 Storage period (days) Multi-chambered bags
Are they a barrier to gas ( air) entry into chambers before and after mixing ? *Greater barrier than PVC or EVA. *Poorer barrier than “multi-layered” bags
Gas entry from atmosphere prevented by gas-impermeable overwrap- until broken!
Each chamber / solution in un-opened bag is oxygen-free. Multi-chambered bags – shelf lives after removing outer wrap
Nutriflex ®+ additional electrolytes, vitamins and trace elements
Shelf life depends on vitamin source: Cernavit ® 7 days @2-8’C+ 1 day at RT Solivito N ® 6 days @2-8’C+1 day at RT
Unaffected by : Bag volume ( 1250-2500 ml regimens) PN formulation ( Lipid Peri; Lipid Plus etc.) Estimating ascorbic acid losses
Oxygen load – 1litre glucose or saline – leads to 50 mg ascorbic acid loss Air in bag – 10 ml air leads to loss of 20 mg ascorbic acid EVA bag – transmission rate leads to loss of 10 mg ascorbic acid /day Multilayered bag – no losses by transmission.
Allwood M.C. & Kearney,M.)1998).. Nutrition;14:687. Degradation of Ascorbic Acid in Synthamin containing PN mixture in multi-layer bag (cernevit®)
100 90 80 70 60 50 40 30 20
10 % Ascorbic Acid remaining AcidAscorbic % 0 0 5 10 15 20 25 Days storage
Total Ascorbic Acid Dehydro Ascorbic Acid Ascorbic Acid
Allwood,M.C.(1984).J.Clin.Hosp.Pharm:9;75 Ensuring ascorbic acid requirements Use multi-layered ( gas-impermeable) bags Remove all air before sealing Top-up with ascorbic acid injection for larger volume PN mixtures ( over 2-2.5 litres) Shelf lives for complete PN mixtures including micro-nutrients ( in M/L bags) – recommend 21 days Can I add extra micro-nutrients?
Trace elements
Based on pharmaceutical considerations - Recommend double “ normal*” quantities can be added :
Selenium as Na selenite approx.0.8umol Zinc as Zn sulphate approx. 100 umol Iron as Fe chloride 20 umol
* ie. based on Additrace or Decan Micronutrients contd.
Vitamins
1. Using multi-vitamin products ( Cernavit ®, solivito N ®, Vitlipid ® ) – no constraints. But Vitlipid ® only to all-in-one mixture !
2. Using separate vitamin sources – Folic acid 15 mg Biotin yes Ascorbic acid 200 mg