1. Background

A Study into Upper and Lower pH Limits of Intravenous Products Delivered by Infusion

Koosh Patel1, Ben Forbes1 and Mike Cram2

1King’s College London, London, UK

2Drug Product Design, Pfizer Research and Development, Sandwich, UK

Acknowledgements and ReferencesMany thanks to Mike Cram, (Pfizer; Sandwich, Kent, UK) for development of study.

Many thanks to the liquids community at drug product design (Pfizer; Sandwich, Kent, UK) for providing the

resources and ideas for the study.

Many thanks to Ben Forbes, (KCL, London, UK) for arranging the placement at Pfizer.

(1) Stranz M, Kastango ES. A Review of pH and Osmolarity. Int J Pharm Compd 2002;6(3):216.

(2) Lee Y, Zocharski PD, Samas B. An intravenous formulation decision tree for discovery compound formulation development. Int J Pharm 2003 3/6;253(1–2):111-119.

(3) Shi Y, Porter W, Merdan T, Li LC. Recent advances in intravenous delivery of poorly water-soluble compounds. Expert Opin Drug Delivery 2009 Dec;6(12):1261-1282.

(4) University College London Hospitals Foundation NHS Trust. Pharmacy Dept. UCL Hospitals injectable medicines administration guide. 3rd ed. Oxford: Wiley-Blackwell; 2010.

(5) Trissel LA. Handbook on injectable drugs. 13th ed. Bethesda, MD.: American Society of Health-System Pharmacists; 2005.

(6) Physicians' Desk Reference 2003. 57th ed. Montvale, NJ: Thomson Pdr; 2003.

(7) Anon. Summary of product characteristics. Available at: https://www.medicines.org.uk/emc/. Accessed October 15, 2012.

2. Purpose

> The aim was to build confidence in the

development of high and low pH infusions and

bolus injections products.

> To achieve this, current marketed intravenous

products formulated at very low and high pH

were studied.

> The objectives were to conduct an extensive

literature search and supporting laboratory

experiments to construct a formulation risk

assessment database for novel compounds.

> The database will consist of formulation

properties (e.g. pH, osmolality, volume)

physicochemical properties (e.g. pKa, log P)

excipients, rate and site of administration.

> This is to provide precedence for novel

compounds formulated at high and low pH.

3. Method

Twenty products identified as having extreme pH

and high volumes of administration were

investigated. The study included literature and

measured values:

Literature primary sources: Handbook of

Injectable Drugs (5), PDR (6), Product Package

Inserts and SPCs (7) were used to find the pKa,

log P, pH, volume, tonicity, excipients, rate of

infusion and site of administration.

Measured: Each lyophile was reconstituted in

accordance to the package insert and the pH and

osmolality of the resulting solution measured.

The pH and osmolality were measured again

after the recommended dilution prior to infusion.

Some products were compatible with more than

one diluent and therefore more than one vial was

prepared and tested for each dilution.

4. Results

Product pH values from literature

All the products, except clarithromycin, lie

outside the generally accepted pH range (Figure

2). The values were of the initial solution; the pH

of the diluted infusion were not found in literature.

Product volumes from literature

The volume of the initial reconstituted vial or

concentrated solution ranged from 1 to 25 ml.

Acid dissociation constant, pKa

Many low pH products formulated at a pH two

units below pKa (fully ionised), whilst most high

pH were not in this region (Figure 3).

Octanol: water partition coefficient, log P

Overall a greater proportion of drugs were found

to be lipophilic, with a log P greater than 0.

4. Results (Continued)

Measured pH values

The initial solution pH fit within the ranges from

published sources. The pH of the infusion

(unavailable in literature) was found to be lower

than the initial pH and varied with the diluents

used to prepare the product (Figure 4).

Measured osmolality

Reconstitution of the lyophiles with sodium

chloride 0.9% was hypertonic and with water for

irrigation was hypotonic (Figure 5). The final

preparations were isotonic around 300 mOsm.

Rate and Site of administration

Most of the products were instructed to be

infused slowly over an extended period of time

and administered into a central or large

peripheral vein.

Application to novel compounds

Development of compound X (Figure 4) was not

supported by high pH infusions.

Development of compound Y (Figure 1) is

precedented by marketed low pH products.

5. Future Work

> Collect irritancy data such as phlebitis risk to

help understand which factor(s) (e.g. pH or

osmolality) is responsible for pain.

> Perform titration experiments to understand

buffer capacity and how drug behaves in blood.

> Compare generics to branded products as

different manufacturers may incorporate different

excipients.

> Prepare infusions with other compatible

diluents such as Ringer’s or Hartmann’s solution.

6. Conclusion

The key outcome was the construction of a map

of extremely high and low pH of 20 intravenous

products, which lie outside the current

physiologically acceptable guidelines.

The data has been applied to two examples to

demonstrate the study’s use in providing

precedence to assess the risk of developing a

novel formulation at extreme pH.

This will help develop a risk to benefit profile for

formulators to consider formulating at high/ low

pH as an extra strategy to solubilise drugs.

Gaps were found in published literature for the

final diluted pH and other physicochemical

properties. Inconsistencies were also seen

between resources. Therefore literature values

need to be verified by measurement to use for

development of novel formulations; which has

been started with this study.

In the current portfolio of

drugs in development,

industry are finding a

number of compounds with

poor aqueous solubility.

One strategy to improve

solubility is adjustments in

pH.

However lack of solubility

at pH of interest leads to

formulations outside the

pH guidelines (1-4).

Very high or low pH

outside the current

formulation guidelines are

a cause for concern and

impede development.

Little to no support is

present in the literature to

provide precedence for

formulating outside the

current pH limits for

intravenous products.Figure 1: Current guidelines for the formulation pH of

intravenous products

Figure 2: The relationship between the initial intravenous preparation volume and

pH (range of pHs available in the literature are shown as error bars).

Figure 3: The relationship between the pKa and formulation pH of intravenous

products.

Figure 4: The changes in pH and volume during preparation of intravenous

products for infusion measured after reconstitution of the vials (recon) and after

preparation for infusion (dilute).

Figure 5: The pH and osmolality of intravenous products measured after

reconstitution of the vials (recon) and after preparation for infusion (dilute).