Ziprasidone (CP 88059; CP-88,059; CP-88,059-01; Geodon; Zeldox; Zipwell) HCl, the hydrochloride salt of Ziprasidone, is a novel and potent dopamine and serotonin (5-HT) receptor antagonist with antipsychotic effects. It is authorized for the treatment of acute mania, mixed states linked to bipolar disorder, and schizophrenia and bipolar illness. When treating schizophrenia patients who respond best to treatment consisting solely of ziprasidone, its intramuscular injection form is authorized for use in cases of acute agitation. According to theories about ziprasidone's mode of action, serotonin type 2 (5HT2) and dopamine type 2 (D2) antagonistic interactions together mediate the drug's effectiveness in treating schizophrenia. The exact mechanism by which ziprasidone treats bipolar disorder is unknown, as it is with other medications that are effective in treating the condition.

Physicochemical Properties

Molecular Formula	C21H22CL2N4OS
Molecular Weight	449.4
Exact Mass	448.089
Elemental Analysis	C, 56.13; H, 4.93; Cl, 15.78; N, 12.47; O, 3.56; S, 7.13
CAS #	122883-93-6
Related CAS #	Ziprasidone; 146939-27-7; Ziprasidone-d8; 1126745-58-1; Ziprasidone hydrochloride monohydrate; 138982-67-9; Ziprasidone mesylate trihydrate; 199191-69-0; Ziprasidone mesylate; 185021-64-1
PubChem CID	219099
Appearance	Solid powder
LogP	4.751
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	4
Heavy Atom Count	29
Complexity	573
Defined Atom Stereocenter Count	0
SMILES	ClC1=CC2=C(CC(N2)=O)C=C1CCN(CC3)CCN3C4=NSC5=C4C=CC=C5.Cl
InChi Key	NZDBKBRIBJLNNT-UHFFFAOYSA-N
InChi Code	InChI=1S/C21H21ClN4OS.ClH/c22-17-13-18-15(12-20(27)23-18)11-14(17)5-6-25-7-9-26(10-8-25)21-16-3-1-2-4-19(16)28-24-21;/h1-4,11,13H,5-10,12H2,(H,23,27);1H
Chemical Name	5-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloro-1,3-dihydroindol-2-one;hydrochloride
Synonyms	CP-88059; CP88059; CP88059 mesylate; Ziprasidone mesylate; CP 88059; CP-88,059; CP-88,059-01; Geodon; Zeldox; Zipwell
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	Rat 5-HT2A ( Ki = 0.42 nM ); Rat 5-HT1A Receptor ( Ki = 3.4 nM ); Rat D2 Receptor ( Ki = 4.8 nM )
ln Vitro	In vitro activity: Ziprasidone has high affinity for human 5-HT receptors and for human dopamine D(2) receptors. Ziprasidone exhibits agonistic properties towards 5-HT(1A) receptors and antagonistic properties towards 5-HT(2A), 5-HT(2C), and 5-HT(1B/1D) receptors. Similar to the antidepressant imipramine, ziprasidone inhibits the uptake of 5-HT and norepinephrine by neurons. [1] In stable transfected HEK-293 cells, ziprasidone inhibits wild-type hERG current in a concentration- and voltage-dependent manner with an IC(50) of 120 nM. When assessed using the envelope of tails test (+30mV) or during a depolarizing voltage (-20 or +30mV), ziprasidone exhibits a minimal tonic block of hERG current. At -50mV, ziprasidone considerably lengthens the slow component of hERG current deactivation's time constant. [2]
ln Vivo	Ziprasidone blocks wild-type hERG current less potently, with an IC(50) of 2.8 mM in Xenopus oocytes. [2] Ziprasidone has an inherent protective mechanism against drug-induced increases in food intake in rats, as evidenced by its ability to suppress the significant increases in food intake caused by olanzapine[2]. Rat hippocampal regions (CA1, CA3, and dentate gyrus, DG) exhibit significant increases in NGF and ChAT immunoreactivity when treated with ziprasidone [3]. As with the atypical antipsychotics clozapine (ED50 = 250 mg/kg i.v.) and olanzapine (ED50 = 1000 mg/kg i.v.), ziprasidone dose-dependently slows raphe unit activity in anesthetized rats.[5]
Cell Assay	Cell Line: HEK-293 cells Concentration: 0-500 nM Incubation Time: 150 seconds Result: Blocked wild-type hERG current in a voltage- and concentration-dependent manner (IC50 = 120 nm).
Animal Protocol	Eight-week-old female Sprague-Dawley rats weighing 200 to 250 g 20 mg/kg Oral gavage; 20 mg/kg; once daily; 7 weeks
Toxicity/Toxicokinetics	Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Because there is little published experience with ziprasidone during breastfeeding, other antipsychotic agents may be preferred, especially while nursing a newborn or preterm infant. A safety scoring system finds ziprasidone possible to use cautiously during breastfeeding. Infants breastfed during maternal use of ziprasidone should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms, such as tremors and abnormal muscle movements. ◉ Effects in Breastfed Infants A woman took ziprasidone 40 mg and citalopram 60 mg daily throughout pregnancy and postpartum. She breastfed extensively, except for occasional formula feedings by others. At 6 months of age, a pediatrician found the infant to be healthy with normal growth and development. Patients enlisted in the National Pregnancy Registry for Atypical Antipsychotics who were taking a second-generation antipsychotic drug while breastfeeding (n = 576) were compared to control breastfeeding patients who were not treated with a second-generation antipsychotic (n = 818). Of the patients who were taking a second-generation antipsychotic drug, 60.4% were on more than one psychotropic. A review of the pediatric medical records, no adverse effects were noted among infants exposed or not exposed to second-generation antipsychotic monotherapy or to polytherapy. The number of women taking ziprasidone was not reported. ◉ Effects on Lactation and Breastmilk Prolactin elevation has occurred during ziprasidone treatment, and galactorrhea has been reported, often in adolescents. However, prolactin elevation might be more transient and less severe than with phenothiazines. The prolactin level in a mother with established lactation may not affect her ability to breastfeed. Patients enlisted in the National Pregnancy Registry for Atypical Antipsychotics who were taking a second-generation antipsychotic drug while breastfeeding (n = 576) were compared to control breastfeeding patients who had primarily diagnoses of major depressive disorder and anxiety disorders, most often treated with SSRI or SNRI antidepressants, but not with a second-generation antipsychotic (n = 818). Among women on a second-generation antipsychotic, 60.4% were on more than one psychotropic compared with 24.4% among women in the control group. Of the women on a second-generation antipsychotic, 59.3% reported “ever breastfeeding” compared to 88.2% of women in the control group. At 3 months postpartum, 23% of women on a second-generation antipsychotic were exclusively breastfeeding compared to 47% of women in the control group. The number of women taking ziprasidone was not reported.
References	[1]. Eur J Pharmacol . 2001 Aug 17;425(3):197-201. [2]. Biochem Pharmacol . 2006 Jan 12;71(3):278-86. [3]. Eur J Pharmacol . 2004 Nov 28;505(1-3):253-4. [4]. J Pharmacol Exp Ther . 2006 Aug;318(2):709-24. [5]. Neuropsychopharmacology . 1999 Nov;21(5):622-31.
Additional Infomation	Ziprasidone Hydrochloride is the hydrochloride salt form of ziprasidone, a benzothiazolylpiperazine derivative and an atypical antipsychotic agent with an antischizophrenic property. Ziprasidone hydrochloride functions as an antagonist at the dopamine D2 and serotonin 5-HT2A and 5-HT1D receptors, and as an agonist at the 5-HT1A receptor. Ziprasidone hydrochloride also inhibits synaptic reuptake of serotonin and norepinephrine. The mechanism of action by which ziprasidone hydrochloride exerts its antischizophrenic effect is unknown but is potentially mediated through a combination of dopamine D2 and serotonin 5-HT2 antagonism. This agent also has antagonistic activity against histamine H1 and alpha-1-adrenergic receptors. See also: Ziprasidone (has active moiety).

Solubility Data

Solubility (In Vitro)

DMSO: ~90 mg/mL (~200.3 mM) Water: <1 mg/mL Ethanol: <1 mg/mL

Solubility (In Vivo)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.2252 mL	11.1259 mL	22.2519 mL
	5 mM	0.4450 mL	2.2252 mL	4.4504 mL
	10 mM	0.2225 mL	1.1126 mL	2.2252 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.