Zirconium propionate

Dissociation constant

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

dissociation constant

Remarks:

dissociation of salts into individual ions

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Qualifier:

no guideline followed

Principles of method if other than guideline:

zero-sink test that measures the dissociation of the metal carboxylate substance in two contrasting test media (low and neutral pH) based on the free metal ion concentration in the presence of a selective adsorbent that acts as a zero-sink for the metal cation

GLP compliance:

no

Dissociating properties:

yes

No.:

#1

Temp.:

20 °C

Remarks on result:

other: >8±12% dissociation after 1h in simulated gastric fluid (pH 1.5)

No.:

#2

Temp.:

20 °C

Remarks on result:

other: >95% dissociation after 1h in simulated interstitial fluid (pH 7.4)

Simulated gastric fluid 

Solution composition

The measured metal concentration of the reference compound and metal carboxylate (MC) in the gastric medium is given in Table 5. The percentage dissolved material of the MC at 1 g compound/L is high (82% on average), which means that the compound is highly soluble in the gastric fluid. The reference compound is also completely dissolved (> 89% on average) in the gastric fluid. 

Table 5 Measured total Zr concentration (C_Zr) dissolved during 12h in the simulated gastric fluid and percent solubility (f_sol) ± standard deviation. The nominal concentrations are the expected concentrations in solution based on the metal content of the compound and using the weighted mass of the compounds and volume of stock solution used to prepare the test solutions. 

	Measured	Nominal
Compound	CZr	CZr	fsol
	μM	μM	%
Reference salt
ZrOCl2.8H2O	9.99±3.45	11.2	89 ± 31
	605±70	548	110 ± 13
MC
(C3H5O2)2Zr	3312 ± 95	4025	82 ± 2

Free metal ion concentration measurement 

For the reference salt (ZrOCl₂.8H₂O) the Zr concentration in solution decreased to < 2% of the initial concentration after 1h due to sorption of the metal on the resin (Table 6). The measured Zr concentration in diluted test solutions is below the quantification limit (LOQ) of the ICP-MS analysis for some test samples. The concentration in solution is the free metal in equilibrium with the resin. Binding of Zr to the resin is instantaneous since almost no differences are observed between measurements at 1h, 6h and 24h. 

The initial Zr concentration of the MC after 12h dissolution in gastric medium, but before addition of the zero sink resin is higher than the concentration range of the reference samples. The Zr concentration in solution of the MC only slightly decreased compared to the initial concentration after 1h due to sorption of Zr on the resin. The MC undergoes a dissociation reaction and exists in equilibrium with its dissociation products. The dissociated metal (or its hydrolysis product such as ZrOH³⁺) reacts with the resin. The metal concentration in solution of the MC is thus, in theory, the free metal in equilibrium with the zero-sink and undissociated MC. The free ion concentration is calculated from the reference compounds and is after 1h equal to 0.16 ± 0.20 μM Zr. This is far below the total measured Zr concentration in solution of 3069 ± 477 μM Zr. After 1h, the calculated dissociated fraction of metal carboxylate is thus only 8 ± 12%. Therefore, this test indicates that the dissociation of the MC in the test media representing gastric fluid is limited. The dissociation did not increase considerably with time, after 24h the dissociated fraction is still only 14 ± 4%. 

One caveat here is that the pH of the solutions slightly differ between the reference solution and that of MC. Indeed, the starting pH in the gastric fluid is 1.5 from the 32 mM HCl. By adding up to 0.6 mM ZrOCl₂, the pH did not largely change. In contrast, by adding 3 mM ZrO-proprionate, 12 mM protons are consumed to convert that to 3 mM Zr⁴⁺ and 6 mM propionic acid and 3 mM H₂O i.e. pH raised from 1.53 to 1.70 by which soluble Zr has reduced positive charge (less Zr⁴⁺, more ZrOH³⁺) and reduced sorption to the cation exchange resin. 

Table 6 Measured Zr concentration in solution at the start (C_Zr,i) and after equilibration (C_Zr,e) and concentration sorbed on the zero sink (C_Zr,s) ± standard deviation at different time points for the reference salts and the MC dissolved in the gastric medium. For the MC, the equilibrium free metal concentration C_Zr is calculated from the reference compounds and used to calculate the dissociated fraction (f_diss). 

		Measured	Measured	Calculated	Calculated
Compound	time	CZr,i	CZr,e	CZr,s	CZr	fdiss
	h	μM	μM	μmol/g	μM	%
Reference salt	0	9.99±3.45
ZrOCl2.8H2O	1		≤0.17*	≥0.98
	6		≤0.17*	≥0.98
	24		0.33	0.97±0.32
Reference salt	0	605±70
ZrOCl2.8H2O	1		0.22±0.07	60.5±7.0
	6		≤0.17*	≥60.5
	24		1.21±0.61	60.4±7.0
MC	0	3312 ± 95
(C3H5O2)2Zr	1		3069 ± 477	24 ± 38	0.16 ± 0.20	8 ± 12
	6		1827 ± 135	149 ± 23	0.84± 0.13	45 ± 6
	24		2865 ± 218	45 ± 12	1.12 ± 0.31	14 ± 4

* For concentrations below the limit of quantification (LOQ), the LOQ is given. 

Simulated interstitial fluid 

Solution composition 

The measured metal concentration of the reference compound and metal carboxylate (MC) in the interstitial fluid is given in Table 7. The percentage dissolved material of the MC at 1 g compound/L is very low (< 0.03%), which means that the compound is highly insoluble in the interstitial fluid. By contrast; the reference compound is (almost) completely dissolved in the interstitial fluid. 

Table 7 Measured total Zr concentration (C_Zr) dissolved during 12h in the simulated interstitial fluid and percent solubility (f_sol) ± standard deviation. The nominal concentrations are the expected concentrations in solution based on the metal content of the compound and using the weighted mass of the compounds and volume of stock solution used to prepare the test solutions. 

	Measured	Nominal
Compound	CZr	CZr	fsol
	μM	μM	%
Reference salt
ZrOCl2.8H2O	2.77± 0.10	2.48	112±4
	22.5 ± 1.5	31.0	73±5
MC
(C3H5O2)2Zr	1.07 ± 0.16	4025	<0.03%

Free metal ion concentration measurement 

For the reference salt (ZrOCl₂.8H₂O) the Zr concentration in solution decreased to < 12% of the initial concentration after 1h due to sorption on the adsorbent (Table 8). For the reference salt, the measured Zr concentration in diluted test solutions is above the quantification limit (LOQ) of the ICP-MS analysis, for the MC, some values are below the LOQ. The Zr concentration in solution in the reference salt is the Zr(OH)₄^° in equilibrium with the adsorbent. Binding of Zr to the adsorbent is almost instantaneous since relatively small differences are observed between measurements at 1h, 6h and 24h. 

The initial Zr concentration of the MC after 12h dissolution in simulated interstitial fluid, but before addition of the zero sink adsorbent is slightly below the concentration of the lowest reference sample. The Zr concentration in solution of the MC decreased to < 16% of the initial concentration after 1h due to sorption of Zr(OH)₄^° on the adsorbent. The Zr concentration in solution of the MC is thus, in theory, the Zr(OH)₄^° in equilibrium with the zero-sink and undissociated MC. The predicted Zr(OH)₄^° concentration after 1h is ≥0.13 μM Zr, this is close to the measured total Zr concentration of 0.17 μM Zr. After 1h, the calculated dissociated fraction of metal carboxylate is thus 95%, after 24h the dissociated fraction slightly decreased to 77± < 1%. Therefore, this test indicates that the MC dissociates fully and instantaneously (< 1h) in the test media representing interstitial fluid in the presence of a Zr adsorbent acting as zero sink. 

Table 8 Measured Zr concentration in solution at the start (C_Zr,i) and after equilibration (C_Zr,e) and concentration sorbed on the zero sink (C_Zr,s) ± standard deviation at different time points for the reference salt and the MC dissolved in the interstitial medium. For the MC, the equilibrium free ion concentration is calculated from the reference compounds and used to calculate the dissociated fraction (f_diss). 

		Measured	Measured	Calculated	Calculated
Compound	time	CZr,i	CZr,e	CZr,s	CZr	fdiss
	h	μM	μM	μmol/g	μM	%
Reference salt	0	2.77± 0.10
ZrOCl2.8H2O	1	0.32 ± 0.03	0.12 ± <0.01
	6		0.17 ± <0.01	0.12 ± <0.01
	24		0.23 ± 0.03	0.13 ± <0.01
Reference salt	0	22.5 ± 1.5
ZrOCl2.8H2O	1		1.48 ± 0.26	1.05 ± 0.09
	6		0.76 ± 0.05	1.09 ± 0.08
	24		0.48 ± <0.01	1.10 ± 0.08
MC	0	1.07 ± 0.16
(C3H5O2)2Zr	1		≤0.17*	≥ 0.04	≥0.13	≥95
	6		≤0.17*	≥ 0.04	≥0.08	≥101
	24		0.35 ± 0.04	0.04 ± 0.01	0.10± <0.01	77 ± < 1

* For concentrations below the limit of quantification (LOQ), the LOQ is given. 

Conclusions:

The zero-sink test indicates that in the simulated gastric medium (pH 1.5), the dissociation of the zirconium propionate is limited to only 8% on average after 1h and 14% after 24h. However, these results would benefit from better correspondence in pH between the reference samples and the metal carboxylate and are expected to be an underestimate of the real dissociation in gastric medium. In the simulated interstitial medium (pH 7.4), the dissociation of zirconium propionate is complete (> 95%) and instantaneous (within 1h). 

Reference 2

Endpoint:

dissociation constant

Remarks:

dissociation of salts into individual ions

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Qualifier:

according to guideline

Guideline:

OECD Guideline 112 (Dissociation Constants in Water)

GLP compliance:

no

Dissociating properties:

yes

No.:

#1

Temp.:

25 °C

Remarks on result:

other: 145±2% dissociation after 1h in water

Solution composition 

The measured concentration of Zr and organic carbon in solution of the metal carboxylate is given in Table 2. Both reference compounds (ZrOCl₂.8H₂O and NaC₃H₅O₂) are completely dissolved after 1h (f_sol ≥ 91% on average) and the Zr or OC concentration in the reference samples remained constant in time (no precipitation). 

The OC concentration in solution of the metal carboxylate (MC) increased over time which means that the dissolution is not instantaneously (Table 2). The measured organic carbon (OC) concentration in solution (Table 2) is high compared to the low Zr concentration. The OC concentration after 24h (4993 μM OC) suggest that the dissolved ligand concentration is 1664 μM C₃H₅O₂, suggesting that the total Zr in solution should be around 832 μM (based on an approximate 1:2 Zr:ligand ratio and molecular formula of Zr(C₃H₅O₂)₂ which is by far not observed. The results suggest that the Zr precipitated (e.g. as ZrO₂) upon dissolution of the MC itself. 

This is different for the ZrOCl₂.8H₂O reference salt, because the pH of that solution was lower than that of the metal carboxylate (pH 2.50 after 24h instead of 3.81), yielding higher soluble Zr products such as Zr(OH)₄^° and ZrOH³⁺ compared to that with the metal carboxylate (Table 2). The measured OC concentration of 4993 μM OC is possible given that the solubility of propionic acid is 1000 g/L at 25°C. The OC concentration of the reference salt NaC₃H₅O₂ (pH 7.21) also indicates the high solubility of the carboxylate. The Zr solubility in the acid gastric fluid and in the interstitial fluid is higher (1.07 -3312 μM Zr) after only 12h compared to that after 24h in water (< 0.03 μM Zr). It is possible that Zr formed complexes with constituents present in the gastric and interstitial media that increased the solubility of the MC in these test media compared to pure water. 

Multi-element analysis with ICP-MS did not show important concentration of other elements in solution, which could interfere with the electrical conductivity measurements. 

Table 2 Measured total concentration Zr (C_Zr,T) or organic carbon (C_OC,T) at 1 g/L and percent solubility (f_sol) ± standard deviation at different samplings. The nominal concentrations are the expected concentrations in solution based on the metal content of the compound and using the weighted mass of the compounds. 

		Measured	Measured	Nominal	Nominal
Compound	time	CZr,T	COC,T	CZr,T	COC,T	fsol,Zr	fsol,OC
	h	μM	μM	μM	μM	%	%
Reference salt
ZrOCl2.8H2O	1	3044 ± 268		3026 ± 26		101± 8
	6	3034 ± 140				100 ± 5
	24	2864 ± 81				95 ± 2
Reference salt
NaC3H5O2	1		29251 ± 298		31630 ± 1727		93 ± 6
	6		29072 ± 121				92 ± 5
	24		28715 ± 317				91 ± 6
MC
(C3H5O2)2Zr	1	< 0.03*	1374 ± 382	5106 ± 164	22232	< 0.001	6.18
	6	< 0.03*	2325 ± 405			< 0.001	10.46
	24	< 0.03*	4993 ± 319			< 0.001	22.46

Electrical conductivity measurements 

The measured electrical conductivity and concentration of metal and ligand for the metal carboxylate and reference compounds in function of time is given in Table 3. The dissociated fraction is calculated from the measured electrical conductivity.

The dissociated fraction of reference compounds is expected to approach 100%, the deviation for both reference compounds (<100% for ZrOCl₂.8H₂O and >100% for NaC₃H₅O₂) might be related to inaccuracies of the model, i.e. the theoretical λ₀ values.

For the dissociation reaction of the metal carboxylate, the ions in solution contributing to the conductivity are RCOO^- and H⁺. Based on the conductivity measurement after 24h, this would mean that the deprotonated ligand concentration RCOO^- is equal to 173 ± 7 μM (Table 3) and the pH equal to 3.76. The pH agrees with the measured pH of 3.81. At pH 3.76, the largest fraction of the ligand is protonated, the ratio of protonated/deprotonated ligand is about 13 based on the pK_a value of propionic acid (pK_a = 4.87). The total predicted ligand concentration C_L,diss derived from the conductivity measurement (protonated + deprotonated ligand) is thus equal to 2387 ± 191 μM (Table 3), from which 173 ± 7 μM is anionic. The expected Zr concentration in solution is thus equal to 2387/2 = 1194 μM Zr, the measured Zr concentration in solution (< 0.02 μM) is much lower than calculated, which points to precipitation of Zr compounds. The total ligand concentration calculated from the measured conductivity C_L,diss (2387 μM) is higher than the total measured ligand concentration in solution (1664 μM), which suggests that no additional undissociated metal carboxylate is present after 24h, i.e. f_diss is equal to 143 ± 2%. The calculations for all time points are given in Table 3. Also for these time points good agreement between calculated and measured pH was found (after 1h, measured pH 4.10 and calculated pH 4.06; after 6h, measured pH 4.02 and calculated pH 3.91). 

Table 3 Measured electrical conductivity (σ) and concentration of metal (C_M,T) and carboxylate ligand (C_L,T) of reference salts and MC (in duplicate) at different points in time. For the ZrOCl₂.8H₂O reference salt, C_i is the dissociated metal concentration calculated from the conductivity data and f_diss the dissociated metal fraction (f_diss) ± standard deviation. For the MC and NaC₃H₅O₂ reference salt, the C_i is the deprotonated carboxylate ligand concentration calculated from the conductivity data. Because of the relatively low pH, for the MC also the protonated ligand concentration is taken into account to obtain f_diss, C_L,diss is the total ligand concentration (protonated + deprotonated).

Compound		Measured	Measured	Measured	Measured	Measured	Measured	Calculated	Calculated	Calculated
		Rep. 1	Rep. 1	Rep. 1	Rep. 2	Rep. 2	Rep. 2
	time	σ	CM,T	CL,T	σ	CM,T	CL,T	Ci	CL,diss	fdiss
	h	μS/cm	mM	mM	μS/cm	mM	mM	mM		%
Reference salt
ZrOCl2.8H2O	1	1574	2.85		1528	3.23		1.82 ± 0.04		60 ± 7
	6	1666	3.13		1614	2.93		1.92 ± 0.04		63 ± 2
	24	1674	2.18		1618	2.92		1.93 ± 0.05		67 ± 4
Reference salt
NaC3H5O2	1	895		9.68	900		9.82	10.4 ± <0.1		107 ± 1
	6	889		9.66	903		9.72	10.4 ± 0.1		108 ± 1
	24	866		9.50	877		9.65	10.1 ± 0.1		106 ± <1
MC			μM	μM		μM	μM	μM	μM
(C3H5O2)2Zr	1	38	< 0.02	548	31	< 0.02	368	88 ± 13	663 ± 176	145 ± 2
	6	51	< 0.02	870	45	< 0.02	679	122 ± 11	1229 ± 206	159 ± 1
	24	70	< 0.02	1740	66	< 0.02	1589	173 ± 7	2387 ± 191	143 ± 2

* values lower than the limit of quantification (LOQ) are replaced by the LOQ 

Conclusions:

The electrical conductivity test in pure water indicates that the dissociation of Zr propionate is complete (≥ 143%) and instantaneous (within 1h).

Description of key information

The electrical conductivity test in pure water indicates that the dissociation of Zr propionate is complete (≥ 143%) and instantaneous (within 1h). The zero-sink test indicates that in the simulated gastric medium (pH 1.5), the dissociation of the zirconium propionate is limited to only 8% on average after 1h and 14% after 24h. However, these results would benefit from better correspondence in pH between the reference samples and the metal carboxylate and are expected to be an underestimate of the real dissociation in gastric medium. In the simulated interstitial medium (pH 7.4), the dissociation of zirconium propionate is complete (> 95%) and instantaneous (within 1h).