Ann Rehabil Med.  2016 Feb;40(1):21-27. 10.5535/arm.2016.40.1.21.

Crystallization of Local Anesthetics When Mixed With Corticosteroid Solutions

• Hwang H
• Park J
• Lee WK
• Lee WH
• Leigh JH
• Lee JJ
• Chung SG
• Lim C
• Park SJ
• Kim K

• KMID: 2155161
• DOI: http://doi.org/10.5535/arm.2016.40.1.21

Abstract

OBJECTIVE
To evaluate at which pH level various local anesthetics precipitate, and to confirm which combination of corticosteroid and local anesthetic crystallizes.
METHODS
Each of ropivacaine-HCl, bupivacaine-HCl, and lidocaine-HCl was mixed with 4 different concentrations of NaOH solutions. Also, each of the three local anesthetics was mixed with the same volume of 3 corticosteroid solutions (triamcinolone acetonide, dexamethasone sodium phosphate, and betamethasone sodium phosphate). Precipitation of the local anesthetics (or not) was observed, by the naked eye and by microscope. The pH of each solution and the size of the precipitated crystal were measured.
RESULTS
Alkalinized with NaOH to a certain value of pH, local anesthetics precipitated (ropivacaine pH 6.9, bupivacaine pH 7.7, and lidocaine pH 12.9). Precipitation was observed as a cloudy appearance by the naked eye and as the aggregation of small particles (<10 µm) by microscope. The amount of particles and aggregation increased with increased pH. Mixed with betamethasone sodium phosphate, ropivacaine was precipitated in the form of numerous large crystals (>300 µm, pH 7.5). Ropivacaine with dexamethasone sodium phosphate also precipitated, but it was only observable by microscope (a few crystals of 10-100 µm, pH 7.0). Bupivacaine with betamethasone sodium phosphate formed precipitates of non-aggregated smaller particles (<10 µm, pH 7.7). Lidocaine mixed with corticosteroids did not precipitate.
CONCLUSION
Ropivacaine and bupivacaine can precipitate by alkalinization at a physiological pH, and therefore also produce crystals at a physiological pH when they are mixed with betamethasone sodium phosphate. Thus, the potential risk should be noted for their use in interventions, such as epidural steroid injections.

Keyword

Crystallization; Local anesthetics; Corticosteroid; Alkalinization; Precipitation

MeSH Terms

Adrenal Cortex Hormones
Anesthetics, Local*
Betamethasone
Bupivacaine
Crystallization*
Dexamethasone
Hydrogen-Ion Concentration
Lidocaine
Sodium
Adrenal Cortex Hormones
Anesthetics, Local
Betamethasone
Bupivacaine
Dexamethasone
Lidocaine
Sodium

Figure

• 

  Fig. 1 Precipitation is observed as a cloudy appearance, when some local anesthetics are mixed with betamethasone sodium phosphate solution. (A) Ropivacaine-HCl+betamethasone sodium phosphate. (B) Bupivacaine-HCl+betamethasone sodium phosphate.

• 

  Fig. 2 Microscopy imaging of precipitation of local anesthetics in variable pH conditions (100×); the scale bar indicates 100 µm. (A–D) Ropivacaine precipitated in solutions of pH 6.9 or higher. Higher precipitation and aggregation were observed at higher pH. (E–H) Bupivacaine began to produce insoluble particles at pH 7.7, and (I–L) lidocaine developed crystals at pH 12.9.

• 

  Fig. 3 Microscopy imaging of local anesthetics mixed with corticosteroid solutions (100×); the scale bar indicates 100 µm. Ropivacaine developed crystals in the mixed solution with either dexamethasone sodium phosphate (B) or betamethasone sodium phosphate (C). Many more and larger crystals were created at higher pH in solution with betamethasone, compared to when in solution with dexamethasone (pH 7.5 and pH 7.0, respectively). Bupivacaine precipitated in solution with betamethasone sodium phosphate (F, pH 7.7), but not in solution with dexamethasone sodium phosphate (E, pH 7.3). Lidocaine did not create any precipitate (H, I). Triamcinolone acetate did not induce precipitation of any local anesthetics tested, but the particles of triamcinolone itself were observed (A, D, G).

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